Substituted benzoazepines as toll-like receptor modulators

ABSTRACT

Provided are compositions and methods useful for modulation of signaling through the Toll-like receptors TLR7 and/or TLR8. The compositions and methods have use in treating or preventing disease, including cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft-verses-host disease.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 12/859,182, filed on Aug. 18, 2010 (i.e., U.S. Pat. No. 8,524,702),which claims priority to, and the benefit of U.S. Provisional PatentApplication No. 61/234,971 filed on Aug. 18, 2009. The contents of eachof the aforementioned applications are hereby incorporated by referencein their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods and compositions for modulating immunefunction. More specifically, this invention relates to compositions andmethods for modulating TLR7- and/or TLR8-mediated signaling.

2. Description of the State of the Art

Stimulation of the immune system, which includes stimulation of eitheror both innate immunity and adaptive immunity, is a complex phenomenonthat can result in either protective or adverse physiologic outcomes forthe host. In recent years there has been increased interest in themechanisms underlying innate immunity, which is believed to initiate andsupport adaptive immunity. This interest has been fueled in part by therecent discovery of a family of highly conserved pattern recognitionreceptor proteins known as Toll-like receptors (TLRs) believed to beinvolved in innate immunity as receptors for pathogen associatedmolecular patterns (PAMPs). Compositions and methods useful formodulating innate immunity are therefore of great interest, as they mayaffect therapeutic approaches to conditions involving autoimmunity,inflammation, allergy, asthma, graft rejection, graft versus hostdisease (GvHD), infection, cancer, and immunodeficiency.

Toll-like receptors (TLRs) are type I transmembrane proteins that alloworganisms (including mammals) to detect microbes and initiate an innateimmune response (Beutler, B., Nature 2004, 430:257-263). They containhomologous cytoplasmic domains and leucine-rich extracellular domainsand typically form homodimers that sense extracellular (or internalized)signals and subsequently initiate a signal transduction cascade viaadaptor molecules such as MyD88 (myeloid differentiation factor 88).There is such high homology in the cytoplasmic domains of the TLRs that,initially, it was suggested that similar signaling pathways exist forall TLRs (Re, F., Strominger, J. L., Immunobiology 2004, 209:191-198).Indeed, all TLRs can activate NF-kB and MAP kinases; however, thecytokine/chemokine release profiles derived from TLR activation appearsunique to each TLR. Additionally, the signaling pathway that TLRsstimulate is very similar to the pathway that the cytokine receptorIL-1R induces. This may be due to the homology that these receptorsshare, i.e., TIR (Toll/IL-1R homology) domains. Once the TIR domain isactivated in TLRs and MyD88 is recruited, activation of the IRAK familyof serine/threonine kinases results which eventually promotes thedegradation of Ik-B and activation of NF-kB (Means T. K., et al. LifeSci. 2000, 68:241-258). While it appears that this cascade is designedto allow extracellular stimuli to promote intracellular events, there isevidence that some TLRs migrate to endosomes where signaling can also beinitiated. This process may allow for intimate contact with engulfedmicrobes and fits with the role that these receptors play in the innateimmune response (Underhill, D. M., et al., Nature 1999, 401:811-815).This process might also allow host nucleic acids, released by damagedtissues (for example, in inflammatory disease) or apoptosis to trigger aresponse via endosomal presentation. Among mammals, there are 11 TLRsthat coordinate this rapid response. A hypothesis put forward years ago(Janeway, C. A., Jr., Cold Spring Harb. Syrup. Quant. Biol. 1989,54:1-13) that the innate immune response initiates the adaptive immuneresponse through the pattern of TLR activation caused by microbes hasnow been substantiated. Thus, the pathogen-associated molecular patterns(PAMPs) presented by a diverse group of infectious organisms results ina innate immune response involving certain cytokines, chemokines andgrowth factors followed by a precise adaptive immune response tailoredto the infectious pathogen via antigen presentation resulting inantibody production and cytotoxic T cell generation.

Gram-negative bacterial lipopolysaccharide (LPS) has long beenappreciated as an adjuvant and immune-stimulant and as a pharmacologicaltool for inducing an inflammatory reaction in mammals similar to septicshock. Using a genetic approach, TLR4 was identified as the receptor forLPS. The discovery that LPS is an agonist of TLR4 illustrates theusefulness of TLR modulation for vaccine and human disease therapy(Aderem, A.; Ulevitch, R. J., Nature 2000, 406:782-787). It is nowappreciated that various TLR agonists can activate B cells, neutrophils,mast cells, eosinophils, endothelial cells and several types ofepithelia in addition to regulating proliferation and apoptosis ofcertain cell types.

To date, TLR7 and TLR8, which are somewhat similar, have beencharacterized as receptors for single-stranded RNA found in endosomalcompartments and thus thought to be important for the immune response toviral challenge. Imiquimod, an approved topical anti-viral/anti-cancerdrug, has recently been described as a TLR7 agonist that hasdemonstrated clinical efficacy in certain skin disorders (Miller R. L.,et al., Int. J. Immunopharm. 1999, 21:1-14). This small molecule drughas been described as a structural mimetic of ssRNA. TLR8 was firstdescribed in 2000 (Du, X., et al., European Cytokine Network 2000(September), 11(3):362-371) and was rapidly ascribed to being involvedwith the innate immune response to viral infection (Miettinen, M., etal., Genes and Immunity 2001 (October), 2(6):349-355).

Recently it was reported that certain imidazoquinoline compounds havingantiviral activity are ligands of TLR7 and TLR8 (Hemmi H., et al. (2002)Nat. Immunol. 3:196-200; Jurk M., et al. (2002) Nat. Immunol. 3:499).Imidazoquinolines are potent synthetic activators of immune cells withantiviral and antitumor properties. Using macrophages from wildtype andMyD88-deficient mice, Hemmi et al. recently reported that twoimidazoquinolines, imiquimod and resiquimod (R848), induce tumornecrosis factor (TNF) and interleukin-12 (IL-12) and activate NF-icBonly in wildtype cells, consistent with activation through a TLR (HemmiH., et al. (2002) Nat. Immunol. 3:196-200). Macrophages from micedeficient in TLR7 but not other TLRs produced no detectable cytokines inresponse to these imidazoquinolines. In addition, the imidazoquinolinesinduced dose-dependent proliferation of splenic B cells and theactivation of intracellular signaling cascades in cells from wildtypebut not TLR7−/− mice. Luciferase analysis established that expression ofhuman TLR7, but not TLR2 or TLR4, in human embryonic kidney cellsresults in NF-KB activation in response to resiquimod. The findings ofHemmi et al. thus suggest that these imidazoquinoline compounds arenon-natural ligands of TLR7 that can induce signaling through TLR7.Recently it was reported that R848 is also a ligand for human TLR8 (JurkM., et al. (2002) Nat. Immunol. 3:499).

In view of the great therapeutic potential for compounds that modulatetoll-like receptors, and despite the work that has already been done,there is a substantial ongoing need to expand their use and therapeuticbenefits.

SUMMARY OF THE INVENTION

The compositions described herein are useful for modulating immuneresponses in vitro and in vivo. Such compositions will find use in anumber of clinical applications, such as in methods for treating orpreventing conditions involving unwanted immune activity, includinginflammatory and autoimmune disorders.

Specifically, the invention relates to a compound having the formula I:

or a tautomer, enantiomer or salt thereof, wherein: Y is substitutedaryl, heteroaryl, or substituted heteroaryl, wherein said substitutedaryl or substituted heteroaryl is substituted with one or more groupsindependently selected from CN, OH, —C(═O)R⁹, halogen, and—CH═CHC(═O)R⁹;

R⁹ is selected from alkyl, OR¹⁵, and NR¹⁰R¹¹;

R¹⁵ is selected from H, alkyl, and —CH₂O(alkyl),

R¹⁰ and R¹¹ are each independently alkyl, wherein said alkyl isoptionally substituted with —OH or R¹⁰ and R¹¹ together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein said heterocyclic ring is optionally substituted with one ormore —OH;

R² is selected from OR¹⁴ and NR⁶R⁷;

R⁶ and R⁷ are each independently selected from H, alkyl, cycloalkyl,heterocycloalkyl or benzyl, wherein said alkyl, cycloalkyl, or benzyl isoptionally substituted with one or more groups independently selectedfrom —F, —OR⁸, —NR¹²SO₂R¹³, —C(═O)NR¹²R¹³ or R⁶ and R⁷ together with thenitrogen atom to which they are attached form a heterocyclic ring,further wherein said heterocyclic ring is optionally substituted withone or more —OH;

R⁸ is selected from hydrogen and alkyl, and

R¹², R¹³ and R¹⁴ are each independently selected from H and alkyl,wherein said alkyl is optionally substituted with —OH;

provided that

a) when Y is aryl substituted with

then R² is not —OCH₂CH₃ (—OEt),

or

b) when Y is aryl substituted with —C(═O)R⁹, and R⁹=NR¹⁰R¹¹, and R¹⁰ andR¹¹ together with the nitrogen atom to which they are attached form anunsubstituted pyrrolidine ring, then R² is not —OEt or —N(propyl)₂.

The invention also relates to a compound having the formula II:

or a tautomer, enantiomer or salt thereof, wherein W is H or —OH; Z is Hor —OH; n is 1 or 2, and R² is as defined in formula I; provided thatwhen W and Z are both H and n is 1, then R² is not —OEt or —N(propyl)₂.

The invention also relates to a compound having the formula III:

or a tautomer, enantiomer or salt thereof, wherein

T is CH, CZ, or N;

U is CH, CZ, or N;

V is CH, CZ, or N;

X is CH, CZ, or N;

W is CH, CZ, or N;

Z is selected from halogen, —CN, —CONR¹⁶R¹⁷, —COOR¹⁸, —CH═CHCOOR¹⁸, and—OR¹⁹;

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected from H, alkyl,and —CH₂O(alkyl); and R² is as defined in formula I.

The invention also relates to a compound having the formula IV:

or a tautomer, enantiomer or salt thereof, wherein R² is as defined informula I.

The invention also relates to a compound having the formula V:

or a tautomer, enantiomer or salt thereof, wherein U is N or CZ, and Zis halogen; and R² is as defined in formula I.

The invention also relates to a compound having the formula VI:

or a tautomer, enantiomer or salt thereof, wherein

J is independently selected from halogen, —C(═O)R⁹ and —CH═CHC(═O)R⁹;

p is selected from 1, 2, and 3; and R² is as defined in formula I;

provided that when p is 1 and J is

attached at the 4-position of the aryl ring, then R² is not —OEt, andfurther provided that when p is 1 and J is

attached at the 4-position of the aryl ring, then R² is not —OEt or—N(propyl)₂.

The invention also relates to a compound having the formula VII:

or a tautomer, enantiomer or salt thereof, wherein:

Y is substituted aryl or substituted heteroaryl, wherein said aryl orheteroaryl is substituted with one or more groups independently selectedfrom —C(═O)R⁹, halogen, and —CH═CHC(═O)R⁹;

R⁹ is selected from alkyl, OR¹⁵, and NR¹⁰R¹¹;

R¹⁵ is selected from H, alkyl, and —CH₂O(alkyl);

R¹⁰ and R¹¹ are each independently alkyl, wherein said alkyl isoptionally substituted with —OH or R¹⁰ and R¹¹ together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein said heterocyclic ring is optionally substituted with one ormore —OH; and

R⁶ and R⁷ are each independently selected from H, alkyl or alkenyl,wherein said alkyl or alkenyl is optionally substituted with one or moregroups independently selected from —F or —OH; provided that when Y isaryl substituted with —C(═O)R⁹, and R⁹=NR¹⁰R¹¹, and R¹⁰ and R¹¹ togetherwith the nitrogen atom to which they are attached form an unsubstitutedpyrrolidine ring, then R⁶ and R⁷ are not both propyl.

The compounds of the invention may be used in combination with otherknown therapeutic agents. Accordingly, this invention also relates topharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention or a salt thereof, in combinationwith a second therapeutic agent.

This invention further provides methods of modulating TLR7- and/orTLR8-mediated signaling, comprising contacting a cell expressing TLR7and/or TLR8 with an effective amount of a compound of the invention, ora salt thereof. In one aspect, the method inhibits TLR7- and/orTLR8-mediated immunostimulatory signaling.

This invention further provides methods of modulating TLR7- and/orTLR8-mediated immunostimulation in a subject, comprising administeringto a patient having or at risk of developing TLR7- and/or TLR8-mediatedimmunostimulation a compound of the invention, or a salt thereof, in anamount effective to inhibit TLR7- and/or TLR8-mediated immunostimulationin the subject.

This invention further provides methods of modulating TLR7- and/orTLR8-mediated immunostimulation in a subject, comprising administeringto a patient having or at risk of developing TLR7- and/or TLR8-mediatedimmunostimulation a compound of the invention, or a salt thereof, in anamount effective to promote TLR7- and/or TLR8-mediated immunostimulationin the subject.

This invention further provides methods of treating or preventing adisease or condition by modulation of TLR7- and/or TLR8-mediatedcellular activities, comprising administering to a warm-blooded animal,such as a mammal, for example a human, having or at risk of developingsaid disease or condition, a compound of the invention, or a saltthereof.

This invention further provides methods of modulating the immune systemof a mammal, comprising administering to a mammal a compound of theinvention, or a salt thereof, in an amount effective to modulate saidimmune system.

Further provided is a compound of the invention, or a salt thereof foruse as a medicament in the treatment of the diseases or conditionsdescribed herein (e.g., cancer, autoimmune disease, infectious disease,inflammatory disorder, graft rejection, and graft-verses-host disease)in a mammal, for example, a human, suffering from such disease orcondition. Also provided is the use of a compound of the invention, asalt thereof, in the preparation of a medicament for the treatment ofthe diseases and conditions described herein (e.g., cancer, autoimmunedisease, infectious disease, inflammatory disorder, graft rejection, andgraft-verses-host disease) in a mammal, for example a human, sufferingfrom such disease or condition.

Further provided is a compound of the invention, or a salt thereof foruse as a medicament in the prevention of the diseases or conditionsdescribed herein (e.g., cancer, autoimmune disease, infectious disease,inflammatory disorder, graft rejection, and graft-verses-host disease)in a mammal, for example, a human, exposed to or predisposed to thedisease or condition, but the mammal does not yet experience or displaysymptoms of such disease or condition. Also provided is the use of acompound of the invention, a salt thereof, in the preparation of amedicament for the treatment of the diseases and conditions describedherein (e.g., cancer, autoimmune disease, infectious disease,inflammatory disorder, graft rejection, and graft-verses-host disease)in a mammal, for example a human, suffering from such disease orcondition.

The disease or condition is selected from, for example, cancer,autoimmune disease, infectious disease, inflammatory disorder, graftrejection, and graft-verses-host disease.

This invention further provides kits comprising one or more compounds ofthe invention, or a salt thereof. The kit may further comprise a secondcompound or formulation comprising a second pharmaceutical agent.

Another aspect provides intermediates for preparing compounds of formulaI. Certain compounds of formula I may be used as intermediates for othercompounds of formula I.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

In certain aspects, the invention provides compositions and methodsuseful for modulating TLR7- and/or TLR8-mediated signaling. Morespecifically, one aspect of this invention provides a compound havingthe formula I:

or a tautomer, enantiomer, or salt thereof, wherein:Y is substituted aryl, heteroaryl, or substituted heteroaryl, whereinsaid substituted aryl or substituted heteroaryl is substituted with oneor more groups independently selected from CN, OH, —C(═O)R⁹, halogen,and —CH═CHC(═O)R⁹;

R⁹ is selected from alkyl, OR¹⁵, and NR¹⁰R¹¹;

R¹⁵ is selected from H, alkyl, and —CH₂O(alkyl),

R¹⁰ and R¹¹ are each independently alkyl, wherein said alkyl isoptionally substituted with —OH or R¹⁰ and R¹¹ together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein said heterocyclic ring is optionally substituted with one ormore —OH;

R² is selected from OR¹⁴ and NR⁶R⁷;

R⁶ and R⁷ are each independently selected from H, alkyl, cycloalkyl,heterocycloalkyl or benzyl, wherein said alkyl, cycloalkyl, or benzyl isoptionally substituted with one or more groups independently selectedfrom —F, —OR⁸, —NR¹²SO₂R¹³, —C(═O)NR¹²R¹³ or R⁶ and R⁷ together with thenitrogen atom to which they are attached form a heterocyclic ring,further wherein said heterocyclic ring is optionally substituted withone or more —OH;

R⁸ is selected from hydrogen and alkyl, and

R¹², R¹³ and R¹⁴ are each independently selected from H and alkyl,wherein said alkyl is optionally substituted with —OH;

provided that

a) when Y is aryl substituted with

then R² is not —OCH₂CH₃ (—OEt),

or

b) when Y is aryl substituted with —C(═O)R⁹, and R⁹=NR¹⁰R¹¹, and R¹⁰ andR¹¹ together with the nitrogen atom to which they are attached form anunsubstituted pyrrolidine ring, then R² is not —OEt or —N(propyl)₂.

For example, a compound of the invention is a compound of formula I,where Y is aryl substituted with

and R² is not —OEt.

In another embodiment, a compound of the invention is a compound offormula I, where Y is aryl substituted with —C(═O)R⁹, R⁹ is NR¹⁰R¹¹, andR¹⁰ and R¹¹ together with the nitrogen atom to which they are attachedform a pyrrolidine ring, and R² is not —OEt or —N(propyl)₂.

In another embodiment, a compound of the invention is a compound offormula I, where Y is substituted aryl, heteroaryl, or substitutedheteroaryl, wherein said substituted aryl or substituted heteroaryl issubstituted with one or more groups independently selected from —C(═O)R⁹and —CH═CHC(═O)R⁹. In another embodiment, a compound of the invention isa compound of formula I, wherein Y is substituted aryl, heteroaryl, orsubstituted heteroaryl, wherein said substituted aryl or substitutedheteroaryl is substituted with —C(═O)R⁹. In another embodiment, acompound of the invention is a compound of formula I, wherein Y issubstituted aryl, heteroaryl, or substituted heteroaryl, wherein saidsubstituted aryl or substituted heteroaryl is substituted with—CH═CHC(═O)R⁹.

One aspect of the invention relates to a compound having the formula II:

or a tautomer, enantiomer, or salt thereof, wherein W is H or —OH; Z isH or —OH; n is 1 or 2 and R² is as described for formula I. In oneembodiment, the invention relates to a compound or salt thereof, havingthe formula II, provided that when W and Z are both H, n is 1, then R²is not —OEt or —N(propyl)₂.

In one embodiment, the invention relates to a compound having formulaIIa:

or a tautomer, enantiomer, or salt thereof, wherein W is H or —OH; Z isH or —OH, and R² is as described for formula I. In one embodiment, theinvention relates to a compound or salt therof, having the formula IIa,provided that when W and Z are both H, then R² is not —OEt or—N(propyl)₂.

In one embodiment, the invention relates to a compound having formulaIIb:

or a tautomer, enantiomer, or salt thereof, wherein W is H or —OH; Z isH or —OH and R² is as described for formula I.

In one embodiment, the invention relates to a compound or salt thereof,having the formula II or IIa, wherein W is H and Z is H. In oneembodiment, the invention relates to a compound or salt thereof, whereinone of W or Z is H and the other is —OH. In one embodiment, theinvention relates to a compound or salt thereof, wherein W is H and Z is—OH. In one embodiment, the invention relates to a compound or saltthereof, wherein W is —OH and Z is H. In one embodiment, the inventionrelates to a compound or salt thereof, wherein W is —OH and Z is —OH.

In one embodiment, the invention relates to a compound or salt thereof,having the formula II or IIa, wherein the stereochemistry of thestereogenic center adjacent to Z is the R-configuration. In oneembodiment, the invention relates to a compound or salt thereof, whereinthe stereochemistry of the stereogenic center adjacent to Z is theS-configuration. In one embodiment, the invention relates to a compoundor salt thereof, wherein the stereochemistry of the stereogenic centeradjacent to W is the R-configuration. In one embodiment, the inventionrelates to a compound or salt thereof, wherein the stereochemistry ofthe stereogenic center adjacent to W is the S-configuration. In oneembodiment, the invention relates to a compound or salt thereof, whereinthe stereochemistry of the stereogenic center adjacent to Z is theR-configuration and the stereocenter adjacent to W is theS-configuration. In one embodiment, the invention relates to a compoundor salt thereof, wherein the stereochemistry of the stereogenic centeradjacent to Z is the R-configuration and the stereocenter adjacent to Wis the R-configuration. In one embodiment, the invention relates to acompound or salt thereof, wherein the stereochemistry of the stereogeniccenter adjacent to Z is the S-configuration and the stereocenteradjacent to W is the R-configuration. In one embodiment, the inventionrelates to a compound or salt thereof, wherein the stereochemistry ofthe stereogenic center adjacent to Z is the S-configuration and thestereocenter adjacent to W is the S-configuration.

One aspect of the invention relates to a compound having the formulaIII:

or a tautomer, enantiomer, or salt thereof, whereinT is CH, CZ, or N;U is CH, CZ, or N;V is CH, CZ, or N,X is CH, CZ, or N,W is CH, CZ, or N,Z is selected from halogen, —CN, —CONR¹⁶R¹⁷, —COOR¹⁸, —CH═CHCOOR¹⁸, and—OR¹⁹; R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected from H,alkyl, and —CH₂O(alkyl); and R² is as described for formula I.

In one embodiment, the invention relates to a compound having theformula IIIa:

or a tautomer, enantiomer, or salt thereof, wherein T is CH, CZ, or N; Zis selected from halogen, —CN, —CONR¹⁶R¹⁷, —COOR¹⁸, —CH═CHCOOR¹⁸, and—OR¹⁹; R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected from H,alkyl, and —CH₂O(alkyl); and R² is as described for formula I.

In one embodiment, the invention relates to a compound, having theformula IIIb:

or a tautomer, enantiomer, or salt thereof,wherein U is CH, CZ, or N; Z is selected from halogen, —CN, —CONR¹⁶R¹⁷,—COOR¹⁸, —CH═CHCOOR¹⁸, and —OR¹⁹; R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are eachindependently selected from H, alkyl, and —CH₂O(alkyl); and R² is asdescribed for formula I.

In one embodiment, the invention relates to a compound having theformula IIIc:

or a tautomer, enantiomer, or salt thereof, whereinV is CH, CZ, or N; Z is selected from halogen, —CN, —CONR¹⁶R¹⁷, —COOR¹⁸,—CH═CHCOOR¹⁸, and —OR¹⁹; R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independentlyselected from H, alkyl, and —CH₂O(alkyl); and R² is as described forformula I.

In one embodiment, the invention relates to a compound having theformula IIId:

or a tautomer, enantiomer, or salt thereof,wherein T, U and V are each independently selected from CH, CZ, or N; Zis selected from halogen, —CN, —CONR¹⁶R¹⁷, —COOR¹⁸, —CH═CHCOOR¹⁸, and—OR¹⁹; R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected from H,alkyl, and —CH₂O(alkyl); and R² is as described for formula I.

In one embodiment, the invention relates to a compound or salt thereof,having the formula III, IIIa, IIIb, IIIc, IIId or salt thereof, whereinZ is CN.

In one embodiment, the invention relates to a compound or salt thereof,having the formula III, IIIa, IIIb, IIIc, IIId or salt thereof, whereinZ is CONR¹⁶R¹⁷. In one embodiment, the invention relates to a compoundor salt thereof, wherein R¹⁶ and R¹⁷ are both alkyl. In one embodiment,the invention relates to a compound or salt thereof, wherein alkyl isselected from methyl and ethyl. In one embodiment, the invention relatesto a compound or salt thereof, wherein alkyl is methyl. In oneembodiment, the invention relates to a compound or salt thereof, whereinalkyl is ethyl.

In one embodiment, the invention relates to a compound or salt thereof,having the formula III, IIIa, IIIb, IIIc, IIId or salt thereof, whereinZ is COOR¹⁸. In one embodiment, the invention relates to a compound orsalt thereof, wherein R¹⁸ is H. In one embodiment, the invention relatesto a compound or salt thereof, wherein R¹⁸ is alkyl. In one embodiment,the invention relates to a compound or salt thereof, wherein alkyl isselected from methyl and ethyl.

In one embodiment, the invention relates to a compound or salt thereof,having the formula III, IIIa, IIIb, IIIc, IIId or salt thereof, whereinZ is OR¹⁹. In one embodiment, the invention relates to a compound orsalt thereof, wherein R¹⁹ is H.

In one embodiment, the invention relates to a compound or salt thereof,having the formula III, IIIa, IIIb, IIIc, IIId or salt thereof, whereinZ is —CH₂O(alkyl). In one embodiment, the invention relates to acompound or salt thereof, wherein alkyl is ethyl.

In one embodiment, the invention relates to a compound or salt thereof,having the formula III, IIIa, IIIb, IIIc, IIId or salt thereof, whereinZ is halogen.

In one embodiment, the invention relates to a compound or salt thereof,having the formula III, IIIa, IIIb, IIIc, IIId or salt thereof, whereinZ is —CH═CHCOOR¹⁸.

One aspect of the invention relates to a compound having the formula IV:

or a tautomer, enantiomer, or salt thereof, wherein R² is as describedfor formula I.

One aspect of the invention relates to a compound having the formula V:

or a tautomer, enantiomer, or salt thereof, wherein U is N or CZ; Z ishalogen; R¹⁸ is selected from H, alkyl, and —CH₂O(alkyl); and R² is asdescribed for formula I. In one embodiment, the invention relates to acompound or salt thereof, wherein R¹⁸ is ethyl or methyl.

One aspect of the invention relates to a compound having the formula VI:

or a tautomer, enantiomer, or salt thereof, wherein

J is independently selected from halogen, —C(═O)R⁹ and —CH═CHC(═O)R⁹;

p is selected from 1, 2, and 3;

R² is selected from OR¹⁴ and NR⁶R⁷;

R⁶ and R⁷ are each independently selected from H, alkyl, cycloalkyl,heterocycloalkyl or benzyl, wherein said alkyl, cycloalkyl, or benzyl isoptionally substituted with one or more groups independently selectedfrom —F, —OR⁸, —NR¹²SO₂R¹³, —C(═O)NR¹²R¹³, or R⁶ and R⁷ together withthe nitrogen atom to which they are attached form a heterocyclic ring,further wherein said heterocyclic ring is optionally substituted withone or more —OH;

R⁸ is selected from hydrogen and alkyl;

R⁹ is selected from alkyl, OR¹⁵, and NR¹⁰R¹¹;

R¹⁰ and R¹¹ are each independently alkyl, wherein said alkyl isoptionally substituted with —OH or R¹⁰ and R¹¹ together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein said heterocyclic ring is optionally substituted with one ormore —OH;

R¹², R¹³ and R¹⁴ are each independently selected from H and alkyl; and

R¹⁵ is selected from H, alkyl, and —CH₂O(alkyl). In one embodiment, theinvention relates to a compound or a salt thereof, having the formulaVI, provided that when p is 1 and J is

attached at the 4-position of the aryl ring, then R² is not —OEt, andfurther provided that when p is 1 and J is

attached at the 4-position of the aryl ring, then R² is not —OEt or—N(propyl)₂.

In one embodiment, the invention relates to a compound or salt thereof,having the formula VI, wherein J is attached at the 4-position of thearyl ring. In one embodiment, the invention relates to a compound orsalt thereof, wherein J is attached at the 3-position of the aryl ring.In one embodiment, the invention relates to a compound or salt thereof,wherein J is attached at the 2-position of the aryl ring. In oneembodiment, the invention relates to a compound or salt thereof, whereinJ is —CH═CHC(═O)R⁹.

In one embodiment, the invention relates to a compound or salt thereof,having the formula VI, wherein J is —C(═O)R⁹. In one embodiment, theinvention relates to a compound or salt thereof, wherein p is 2, one Jis —C(═O)R⁹, and the other J is halogen. In one embodiment, theinvention relates to a compound or salt thereof, wherein R⁹ is OR¹⁵. Inone embodiment, the invention relates to a compound or salt thereof,wherein R¹⁵ is alkyl. In one embodiment, the invention relates to acompound or salt thereof, wherein R¹⁵ is selected from ethyl and methyl.In one embodiment, the invention relates to a compound or salt thereof,wherein one J is —C(═O)R⁹ and the other J is F. In one embodiment, theinvention relates to a compound or salt thereof, wherein R⁹ is OR¹⁵. Inone embodiment, the invention relates to a compound or salt thereof,wherein R¹⁵ is —CH₂O(alkyl).

One aspect of the invention relates to a compound having the formulaVII:

or a tautomer, enantiomer or salt thereof, wherein:

Y is substituted aryl or substituted heteroaryl, wherein said aryl orheteroaryl is substituted with one or more groups independently selectedfrom —C(═O)R⁹, halogen, and —CH═CHC(═O)R⁹;

R⁹ is selected from alkyl, OR¹⁵, and NR¹⁰R¹¹;

R¹⁵ is selected from H, alkyl, and —CH₂O(alkyl);

R¹⁰ and R¹¹ are each independently alkyl, wherein said alkyl isoptionally substituted with —OH or R¹⁰ and R¹¹ together with thenitrogen atom to which they are attached form a heterocyclic ring,wherein said heterocyclic ring is optionally substituted with one ormore —OH; and

R⁶ and R⁷ are each independently selected from H, alkyl or alkenyl,wherein said alkyl or alkenyl is optionally substituted with one or moregroups independently selected from —F or —OH;

provided that when Y is aryl substituted with —C(═O)R⁹, and R⁹=NR¹⁰R¹¹,and R¹⁰ and R¹¹ together with the nitrogen atom to which they areattached form an unsubstituted pyrrolidine ring, then R⁶ and R⁷ are notboth propyl.

In another embodiment, the invention relates to a compound having theformula VII, wherein:

Y is substituted aryl or substituted heteroaryl, wherein said aryl orheteroaryl is substituted with one or more groups independently selectedfrom —C(═O)R⁹, halogen, and —CH═CHC(═O)R⁹;

R⁹ is OR¹⁵;

R¹⁵ is selected from H, alkyl, and —CH₂O(alkyl); and

R⁶ and R⁷ are each independently selected from H, alkyl or alkenyl,wherein said alkyl or alkenyl is optionally substituted with one or moregroups independently selected from —F or —OH.

In another embodiment, the invention relates to a compound having theformula VII, wherein:

Y is substituted aryl, wherein said aryl is substituted with —C(═O)R⁹;

R⁹ is selected from alkyl, OR¹⁵, and NR¹⁰R¹¹;

R¹⁵ is selected from H, alkyl, and —CH₂O(alkyl),

R¹⁰ and R¹¹ together with the nitrogen atom to which they are attachedform a heterocyclic ring, wherein said heterocyclic ring is optionallysubstituted with one or more —OH; and

R⁶ and R⁷ are each independently selected from H, alkyl or alkenyl,wherein said alkyl or alkenyl is optionally substituted with one or moregroups independently selected from —F or —OH; provided that whenR⁹=NR¹⁰R¹¹, and R¹⁰ and R¹¹ together with the nitrogen atom to whichthey are attached form an unsubstituted pyrrolidine ring, then R⁶ and R⁷are not both propyl.

In another embodiment, the invention relates to a compound having theformula VII, wherein R⁶ and R⁷ are each independently alkyl, whereinsaid alkyl is substituted with one or more groups independently selectedfrom —F and —OH. In another embodiment, the invention relates to acompound having the formula VII, wherein R⁶ and R⁷ are eachindependently alkyl, wherein said alkyl is unsubstituted. In anotherembodiment, the invention relates to a compound having the formula VII,wherein Y is substituted aryl. In another embodiment, the inventionrelates to a compound having the formula VII, wherein Y is substitutedphenyl. In another embodiment, the invention relates to a compoundhaving the formula VII, wherein Y is substituted heteroaryl.

In another embodiment, the invention relates to a compound having theformula VIIa:

or a tautomer, enantiomer or salt thereof, wherein:

v is 0, 1, or 2;

R⁶ is selected from H, allyl, prop-1-enyl, and propyl, wherein saidpropyl is optionally substituted with one or more —OH;

R⁷ is selected from allyl, prop-1-enyl, and propyl, wherein said propylis optionally substituted with one or more —OH;

provided that when v is 0, then R⁶ and R⁷ are not both propyl.

In another embodiment, the invention relates to a compound having theformula Vila wherein R⁶ and R⁷ are each independently propyl, whereinsaid propyl is optionally substituted with one or more —OH. In anotherembodiment, the invention relates to a compound having the formula Vilawherein R⁶ and R⁷ are each independently propyl, wherein one of R⁶ or R⁷is substituted with one or more —OH and the other is unsubstituted. Inanother embodiment, the invention relates to a compound having theformula VIIa wherein R⁶ and R⁷ are each unsubstituted propyl. In anotherembodiment, the invention relates to a compound having the formula VIIawherein v is 0. In another embodiment, the invention relates to acompound having the formula Vila wherein v is 1 or 2.

One aspect of the invention relates to a compound or salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —OR¹⁴. In one embodiment, the invention relates toa compound or a salt thereof, wherein R¹⁴ is alkyl. In one embodiment,the invention relates to a compound or a salt thereof, wherein alkyl isethyl.

One aspect of the invention relates to a compound or a salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —NR⁶R⁷. In one embodiment, the invention relates toa compound or a salt thereof, wherein one of R⁶ or R⁷ is H and the otheris alkyl. In one embodiment, the invention relates to a compound or asalt thereof, wherein both R⁶ and R⁷ are each independently alkyl. Inone embodiment, the invention relates to a compound or a salt thereof,wherein each alkyl is independently selected from isopropyl, propyl,isobuytyl, and secbutyl. In one embodiment, the invention relates to acompound or a salt thereof, wherein alkyl is optionally substituted withone or more —OH. In one embodiment, the invention relates to a compoundor a salt thereof, wherein alkyl is substituted with one —OH. In oneembodiment, the invention relates to a compound or a salt thereof,wherein the stereocenter adjacent to the —OH group is theS-configuration.

In one embodiment, the invention relates to a compound or a saltthereof, wherein the stereocenter adjacent to the OH group is theR-configuration. In one embodiment, the invention relates to a compoundor a salt thereof, wherein alkyl is substituted with two —OH. In oneembodiment, the invention relates to a compound or a salt thereof,wherein alkyl is optionally substituted with one or more —O(alkyl). Inone embodiment, the invention relates to a compound or a salt thereof,wherein alkyl is substituted with one —O(alkyl). In one embodiment, theinvention relates to a compound or a salt thereof, wherein alkyl issubstituted two —O(alkyl).

One aspect of the invention relates to a compound or a salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —NR⁶R⁷. In one embodiment, the invention relates toa compound or a salt thereof, wherein one of R⁶ or R⁷ is alkyl, and theother is benzyl. In one embodiment, the invention relates to a compoundor a salt thereof, wherein benzyl is substituted with —OH.

One aspect of the invention relates to a compound or salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —NR⁶R⁷. In one embodiment, the invention relates toa compound or a salt thereof, wherein at least one of R⁶ or R⁷ is alkyl.In one embodiment, the invention relates to a compound or a saltthereof, wherein one alkyl is substituted with —NR¹²SO₂R¹³. In oneembodiment, the invention relates to a compound or a salt thereof,wherein R¹² is H. In one embodiment, the invention relates to a compoundor a salt thereof, wherein R¹³ is methyl.

One aspect of the invention relates to a compound or a salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —NR⁶R⁷. In one embodiment, the invention relates toa compound or a salt thereof, wherein at least one of R⁶ or R⁷ is alkyl.In one embodiment, the invention relates to a compound or a saltthereof, wherein one alkyl is substituted with —C(═O)NR¹²R¹³. In oneembodiment, the invention relates to a compound or a salt thereof,wherein R¹² and R¹³ are both H.

One aspect of the invention relates to a compound or a salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —NR⁶R⁷. In one embodiment, the invention relates toa compound or a salt thereof, wherein at least one of R⁶ or R⁷ is alkyl.In one embodiment, the invention relates to a compound or a saltthereof, wherein alkyl is substituted with halogen.

One aspect of the invention relates to a compound or a salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —NR⁶R⁷. In one embodiment, the invention relates toa compound or a salt thereof, wherein R⁶ and R⁷ are both propyl. In oneembodiment, the invention relates to a compound or a salt thereof,wherein, wherein one of R⁶ or R⁷ is cycloalkyl and the other isheterocycloalkyl. In one embodiment, the invention relates to a compoundor a salt thereof, wherein cycloalkyl is cyclopropyl. In one embodiment,the invention relates to a compound or a salt thereof, whereinheterocycloalkyl is piperidine.

One aspect of the invention relates to a compound or a salt thereof,having the formula I, II, IIa, IIb, III, IIIa, IIIb, IIIc, IIId, IV, V,or VI, wherein R² is —NR⁶R⁷. In one embodiment, the invention relates toa compound or a salt thereof, wherein R⁶ and R⁷ together with thenitrogen atom to which they are attached form a heterocyclic ring. Inone embodiment, the invention relates to a compound, wherein theheterocyclic ring is selected from pyrrolidine and piperidine.

One aspect of the invention relates to a compound or a salt thereof,selected from a compound in Table 1 (formula I). In one embodiment, theinvention relates to a compound or a salt thereof, selected fromCompound 156, 101, 102, 103, 104, 105, 106, 107, 109, 110, 112, 117,119, 120, 174, 176, 178, 127, 128, 129, 130, 182, 115, 121, 122, 126,and 202 (formula II). In one embodiment, the invention relates to acompound or a salt thereof, selected from Compound 101, 102, 103, 104,105, 106, 107, 109, 110, 112, 117, 119, 120, 174, 176, 178, 127, 128,129, 130, 182, 115, 121, 122, and 202 (formula IIa). In one embodiment,the invention relates to a compound or a salt thereof selected fromCompound 126 and 156 (formula IIb). In one embodiment, the inventionrelates to a compound or a salt thereof, selected from Compound 143,146, 154, 155, 124, 125, 134, 137, 139, 188, 190, 195, 202, 206, 207,208, 209, and 220 (formula IIIa). In one embodiment, the inventionrelates to a compound or a salt thereof, selected from Compound 142,145, 147, 133, 136, 138, 186, 187, and 194 (formula IIIb). In oneembodiment, the invention relates to a compound or a salt thereof,selected from Compound 141, 203, and 204 (formula IIIc). In oneembodiment, the invention relates to a compound or a salt thereof,selected from Compound 144 and 135 (formula IV). In one embodiment, theinvention relates to a compound or a salt thereof, selected fromCompound 210, 211, and 212 (formula V). In one embodiment, the inventionrelates to a compound or a salt thereof, selected from Compound 139,220, 211, 187, 190, 203, 204, 206, 207, 208, 212, and 210 (formula VI).In one embodiment, the invention relates to a compound or a saltthereof, selected from Compound 101, 102, 103, 104, 105, 106, 107, 109,110, 117, 124, 125, 126, 127, 128, 129, 130, 138, 139, 220, 186, 182,187, 188, 190, 202, 203, 204, 206, 207, 208, 209, 212, 227, 228, 229,230, 231, 232, 233, 234, 235, 236, 237, 238, and 239 (formula VII). Inone embodiment, the invention relates to a compound or a salt thereof,selected from Compound 101, 104, 105, 106, 109, 110, 127, 128, 129, 130,182, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, and 239(formula VIIa).

One aspect of the invention relates to a salt of a compound of theinvention, wherein the salt is a pharmaceutically acceptable salt.

One aspect of the invention relates to a kit for treating a TLR7- and/orTLR8-mediated condition, comprising:

a) a first pharmaceutical composition comprising a compound of theinvention or a salt thereof; and

b) optionally instructions for use.

In one embodiment, the invention relates to the kit further comprising(c) a second pharmaceutical composition, wherein the secondpharmaceutical composition comprises a second compound for treating aTLR7- and/or TLR8-mediated condition. In one embodiment, the inventionrelates to the kit, further comprising instructions for thesimultaneous, sequential or separate administration of said first andsecond pharmaceutical compositions to a patient in need thereof.

One aspect of the invention relates to a pharmaceutical composition,which comprises a compound of the invention or a salt thereof, togetherwith a pharmaceutically acceptable diluent or carrier.

One aspect of the invention relates to a compound of the invention foruse as a medicament for treating a TLR7 and/or TLR8-mediated conditionin a human or animal. In one embodiment, the invention relates to acompound of the invention or a salt thereof, in the manufacture of amedicament for the treatment of an abnormal cell growth condition in ahuman or animal.

One aspect of the invention relates to a method of treating a TLR7-and/or TLR8-mediated condition, comprising administering to a patient inneed thereof an effective amount of a compound of the invention or asalt thereof.

One aspect of the invention relates to a method of modulating apatient's immune system, comprising administering to a patient in needthereof an effective amount of a compound of the invention or a saltthereof.

The invention includes a compound selected from the compounds listed inTable 1.

TABLE 1 # Chemical Structure 101

102

103

104

105

106

107

112

109

110

115

117

119

120

121

122

132

124

125

126

127

128

129

130

133

134

135

136

137

138

139

154

141

142

143

144

145

146

147

220

155

156

174

176

186

178

211

182

187

188

194

190

195

202

203

204

206

207

208

209

212

210

227

228

229

230

231

232

233

234

235

236

237

238

239

In one aspect, the invention includes a compound, or salt thereof, withan MC₅₀ value ≦25,000 nM for TLR8. In another aspect, the inventionincludes a compound or salt thereof, with an MC₅₀ value ≦10,000 nM forTLR8. In another aspect, the invention includes a compound or saltthereof, with an MC₅₀ value ≦1,000 nM for TLR8. In another aspect, theinvention includes a compound or salt thereof, with an MC₅₀ value ≦100nM for TLR8. In another aspect, the invention includes a compound orsalt thereof, with an MC₅₀ value ≦25 nM for TLR8.

In one aspect, the invention includes a compound or salt thereof, withan MC₅₀ value ≦25,000 nM for TLR7. In another aspect, the inventionincludes a compound or salt thereof, with an MC₅₀ value ≦10,000 nM forTLR7. In another aspect, the invention includes a compound or saltthereof, with an MC₅₀ value ≦1,000 nM for TLR7. In another aspect, theinvention includes a compound or salt thereof, with an MC₅₀ value ≦100nM for TLR7. In another aspect, the invention includes a compound orsalt thereof, with an MC₅₀ value ≦25 nM for TLR7.

In one aspect, the invention does not include a compound or saltthereof, with an MC₅₀>25,000 for TLR7. In one aspect, the invention doesnot include a compound or salt thereof, with an MC₅₀>25,000 for TLR8. Inone aspect, the invention does not include a compound or salt thereof,with MC₅₀ values >25,000 for TLR7 and for TLR8.

Another aspect of the invention relates to soft drugs (also known as“antedrugs”). “Soft drugs” can be defined as biologically activechemical compounds (drugs) which are metabolically deactivated afterthey achieve their therapeutic role at their designed site of action.The use of soft drugs, instead of their non-deactivatable analogs, canavoid unwanted side effects. In one aspect, the metabolic disposition ofthe soft drugs takes place with a controllable rate in a predictablemanner. One embodiment of the invention relates to compounds that aresoft drugs. Specifically, the invention relates to compounds that aredesigned to cleave in vivo, after achieving their therapeutic effect, toa less active moiety. The invention relates to compounds that aredesigned to cleave in vivo, after achieving their therapeutic effect, toa non-toxic moiety. Soft drugs of the invention include compounds suchas Compound 139, 220, 211, 187, 190, 203, 204, 206, 207, 208, 212, and210.

The term “compound of the invention” refers to exemplified compounds andcompounds covered under the formulae described herein.

The term “substituted,” as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

A chemical structure showing a dotted line representation for a chemicalbond indicates that the bond is optionally present. For example, adotted line drawn next to a solid single bond indicates that the bondcan be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical having one to twelve,including one to ten carbon atoms (C₁-C₁₀), one to six carbon atoms(C₁-C₆) and one to four carbon atoms (C₁-C₄), wherein the alkyl radicalmay be optionally substituted independently with one or moresubstituents described below. Examples of alkyl radicals includehydrocarbon moieties such as, but not limited to: methyl (Me, —CH₃),ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl(i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, and 1-octyl.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical having two to 10 carbon atoms (C₂-C₁₀), includingtwo to six carbon atoms (C₂-C₆) and two to four carbon atoms (C₂-C₄),and at least one double bond, and includes, but is not limited to,ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and thelike, wherein the alkenyl radical may be optionally substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. The term “alkenyl” includesallyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms (C₂-C₁₂), including two to 10carbon atoms (C₂-C₁₀), two to six carbon atoms (C₂-C₆) and two to fourcarbon atoms (C₂-C₄), containing at least one triple bond. Examplesinclude, but are not limited to, ethynyl, propynyl, butynyl, pentyn-2-yland the like, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein.

The terms “carbocycle,” “carbocyclyl,” or “cycloalkyl” are usedinterchangeably herein and refer to saturated or partially unsaturatedcyclic hydrocarbon radical having from three to twelve carbon atoms(C₃-C₁₂), including from three to ten carbon atoms (C₃-C₁₀) and fromthree to six carbon atoms (C₃-C₆). The term “cycloalkyl” includesmonocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkylstructures, wherein the polycyclic structures optionally include asaturated or partially unsaturated cycloalkyl fused to a saturated orpartially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl orheteroaryl ring. Examples of cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like. Bicyclic carbocycles have 7 to 12 ring atoms,e.g. arranged as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or10 ring atoms arranged as a bicyclo[5,6] or [6,6] system, or as bridgedsystems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, andbicyclo[3.2.2]nonane. The cycloalkyl may be optionally substitutedindependently at one or more substitutable positions with one or moresubstituents described herein. Such cycloalkyl groups may be optionallysubstituted with, for example, one or more groups independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁ C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl and di(C₁ C₆)alkylamino(C₁-C₆)alkyl.

The term “cycloalkenyl” refers to a partially unsaturated cyclichydrocarbon radical having from three to ten carbon atoms (C₃-C₁₀),including from three to six carbon atoms (C₃-C₆) and having at least onedouble bond within the carbocycle.

The term “heteroalkyl” refers to saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms (C₁-C₁₂),including from one to six carbon atoms (C₁-C₆) and from one to fourcarbon atoms (C₁-C₄), wherein at least one of the carbon atoms isreplaced with a heteroatom selected from N, O, or S, and wherein theradical may be a carbon radical or heteroatom radical (i.e., theheteroatom may appear in the middle or at the end of the radical). Theheteroalkyl radical may be optionally substituted independently with oneor more substituents described herein. The term “heteroalkyl”encompasses alkoxy and heteroalkoxy radicals.

The terms “heterocycloalkyl,” “heterocycle” and “hetercyclyl” are usedinterchangeably herein and refer to a saturated or partially unsaturatedcarbocyclic radical of 3 to 8 ring atoms in which at least one ring atomis a heteroatom selected from nitrogen, oxygen and sulfur, the remainingring atoms being C, where one or more ring atoms may be optionallysubstituted independently with one or more substituents described below.The radical may be a carbon radical or heteroatom radical. The term“heterocycle” includes heterocycloalkoxy. The term further includesfused ring systems which include a heterocycle fused to an aromaticgroup. “Heterocycloalkyl” also includes radicals where heterocycleradicals are fused with aromatic or heteroaromatic rings. Examples ofheterocycloalkyl rings include, but are not limited to, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas.Spiro moieties are also included within the scope of this definition.The foregoing groups, as derived from the groups listed above, may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole may beimidazol-1-yl (N attached) or imidazol-3-yl (C-attached). An example ofa heterocyclic group wherein 2 ring carbon atoms are substituted withoxo (═O) moieties is 1,1-dioxo-thiomorpholinyl. The heterocycle groupsherein are unsubstituted or, as specified, substituted in one or moresubstitutable positions with various groups. For example, suchheterocycle groups may be optionally substituted with, for example, oneor more groups independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆6)alkylamino, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkylor di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “aryl” refers to a monovalent aromatic carbocyclic radicalhaving a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, etc.), which is optionallysubstituted with one or more substituents independently selected from,for example, halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl,heteroaryl and hydroxy. In one embodiment, the aryl is a 6-memberedaryl. For example, aryl is phenyl.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings and includes fused ring systems (at least one ofwhich is aromatic) of 5-10 atoms containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, isobenzofuran-1(3H)-one, andfuropyridinyl. Spiro moieties are also included within the scope of thisdefinition. Heteroaryl groups are optionally substituted with one ormore substituents independently selected from, for example, halogen,lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.

The term “halogen” represents fluorine, bromine, chlorine, and iodine.

The term “oxo” represents ═O.

In general, the various moieties or functional groups of the compoundsof the invention may be optionally substituted by one or moresubstituents. Examples of substituents suitable for purposes of thisinvention include, but are not limited to, oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR″SO₂R′,—SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R, —NR″C(O)OR′, —NR″C(O)R′,—C(O)NR′R″, —NRC(O)NR″, —NRC(NCN)NR′R″, —OR′, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, whereR′, R″ and R′″ are independently H, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl.

An “(alkyl)aryl” group, as used herein, is an aryl substituent that islinked to a compound by a straight chain or branched alkyl group havingfrom one to twelve carbon atoms. In one aspect, the aryl substituent islinked to a compound by a straight chain or branched alkyl group having1-6 carbon atoms. The alkyl moiety of the (alkyl)aryl group isoptionally substituted. In one embodiment, the aryl is a 6-memberedaryl. For example, aryl is phenyl.

An “(alkyl)heterocycloalkyl” group, as used herein, is a heterocyclesubstituent that is linked to a compound by a straight chain or branchedalkyl group having from one to twelve carbon atoms. In one aspect, theheterocycle substituent is linked to a compound by a straight chain orbranched alkyl group having 1-6 carbon atoms. The alkyl moiety of the(alkyl)heterocycle group is optionally substituted.

An “(alkyl)cycloalkyl” group, as used herein, is a cycloalkylsubstituent that is linked to a compound by a straight chain or branchedalkyl group having from one to twelve carbon atoms. In one aspect, thecycloalkyl substituent is linked to a compound by a straight chain orbranched alkyl group having 1-6 carbon atoms. The alkyl moiety of the(alkyl)cycloalkyl group is optionally substituted.

An “(alkyl)cycloalkenyl” group, as used herein, is a cycloalkenylsubstituent that is linked to a compound by a straight chain or branchedalkyl group having from one to twelve carbon atoms. In one aspect, thecycloalkenyl substituent is linked to a compound by a straight chain orbranched alkyl group having 1-6 carbon atoms. The alkyl moiety of the(alkyl)cycloalkenyl group is optionally substituted.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers,diastereomers mixtures, racemic or otherwise, thereof. Accordingly, thisinvention also includes all such isomers, including diastereomericmixtures, pure diastereomers and pure enantiomers of the compounds ofthe formulae described herein.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomer mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. Enantiomers can also be separated by use of a chiral HPLCcolumn. Methods for the determination of stereochemistry and theseparation of stereoisomers are well known in the art (see discussion inChapter 4 of “Advanced Organic Chemistry”, 4th edition, J. March, JohnWiley and Sons, New York, 1992).

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

A single stereoisomer, e.g. an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. Stereochemistly of OrganicCompounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, a-methyl-13-phenylethylamine (amphetamine), and the likewith asymmetric compounds bearing acidic functionality, such ascarboxylic acid and sulfonic acid. The diastereomeric salts may beinduced to separate by fractional crystallization or ionicchromatography. For separation of the optical isomers of aminocompounds, addition of chiral carboxylic or sulfonic acids, such ascamphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid canresult in formation of the diastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, for example a menthyl ester such as (−) menthylchloroformate, in the presence of base, or Mosher ester,a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III, (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). Bymethod (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (Chiral LiquidChromatography (1989) W. J. Lough, Ed., Chapman and Hall, New York;Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

“Tautomer” refers to a compound whose structures differ markedly inarrangement of atoms, but which exist in easy and rapid equilibrium. Itis to be understood that the compounds of the invention may be depictedas different tautomers. It should also be understood that when compoundshave tautomeric forms, all tautomeric forms are intended to be withinthe scope of the invention, and the naming of the compounds does notexclude any tautomer form.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

In addition to compounds of the invention, the invention also includespharmaceutically acceptable salts of such compounds.

A “pharmaceutically acceptable salt,” unless otherwise indicated,includes salts that retain the biological effectiveness of the freeacids and bases of the specified compound and that are not biologicallyor otherwise undesirable. A compound of the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Examples of pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a mineral or organic acid or an inorganic base, suchsalts including sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyn-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, pheylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycollates,tartrates, methanesulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.Since a single compound of the present invention may include more thanone acidic or basic moieties, the compounds of the present invention mayinclude mono, di or tri-salts in a single compound.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an acidic compound,particularly an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid such as glucuronicacid or galacturonic acid, an alpha hydroxy acid such as citric acid ortartaric acid, an amino acid such as aspartic acid or glutamic acid, anaromatic acid such as benzoic acid or cinnamic acid, a sulfonic acidsuch as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base. Examplesof suitable inorganic salts include those formed with alkali andalkaline earth metals such as lithium, sodium, potassium, barium andcalcium. Examples of suitable organic base salts include, for example,ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium,bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine,dibenzylethylenediamine, and the like salts. Other salts of acidicmoieties may include, for example, those salts formed with procaine,quinine and N-methylglucosamine, plus salts formed with basic aminoacids such as glycine, ornithine, histidine, phenylglycine, lysine andarginine.

The present invention also provides salts of compounds of the inventionwhich are not necessarily pharmaceutically acceptable salts, but whichmay be useful as intermediates for preparing and/or purifying compoundsof the invention and/or for separating enantiomers of compounds of theinvention.

The inventive compounds may be prepared using the reaction routes andsynthesis schemes as described in Scheme I, employing the techniquesavailable in the art using starting materials that are readilyavailable.

In Scheme I, compounds of Formula II may be prepared from an alkyl areneof Formula I by treatment with dimethylformamide dimethyl acetal with orwithout the use of pyrollidine (J. Org. Chem., (1986), 51(26),5106-5110) in DMF at 70-90° C. The crude intermediate (not shown) may becleaved to the aldehyde of Formula II with NaI04 in THF/pH 7.2 phosphatebuffer at or around room temperature. The aldehyde of Formula II may beolefinated with phosphonium ylid in toluene at temperatures ranging from70 to 110° C. (1-16 hours) to give compounds of Formula III. Compoundsof Formula IV can be prepared from a compound of Formula III using ironpowder in acetic acid. The reaction may be conducted at temperatures ofabout 90° C. for about 3-14 hours.

It is noted that some of the preparations of compounds of the inventiondescribed herein may require protection of remote functionalities. Theneed for such protection will vary depending on the nature of thefunctionality and the conditions used in the preparation methods and canbe readily determined by those skilled in the art. Suchprotection/deprotection methods are well known to those skilled in theart.

The compounds of the invention find use in a variety of applications.For example, in certain aspects the invention provides methods formodulating TLR7- and/or TLR8-mediated signaling. The methods of theinvention are useful, for example, when it is desirable to alter TLR7-and/or TLR8-mediated signaling in response to a suitable TLR7 and/orTLR8 ligand or a TLR7 and/or TLR8 signaling agonist.

As used herein, the terms “TLR7 and/or TLR8 ligand,” “ligand for TLR7and/or TLR8,” and “TLR7 and/or TLR8 signaling agonist” refer to amolecule, other than a compound of the invention, that interactsdirectly or indirectly with TLR7 and/or TLR8 and induces TLR7- and/orTLR8-mediated signaling. In certain embodiments, a TLR7 and/or TLR8ligand is a natural ligand, i.e., a TLR7 and/or TLR8 ligand that isfound in nature. In certain embodiments, a TLR7 and/or TLR8 ligandrefers to a molecule other than a natural ligand of TLR7 and/or TLR8,e.g., a molecule prepared by human activity.

The term “modulate” as used herein with respect to the TLR7 and/or TLR8receptors means the mediation of a pharmacodynamic response in a subjectby (i) inhibiting or activating the receptor, or (ii) directly orindirectly affecting the normal regulation of the receptor activity.Compounds that modulate the receptor activity include agonists,antagonists, mixed agonists/antagonists and compounds that directly orindirectly affect regulation of the receptor activity.

The term “agonist” refers to a compound that, in combination with areceptor (e.g., a TLR), can produce a cellular response. An agonist maybe a ligand that directly binds to the receptor. Alternatively, anagonist may combine with a receptor indirectly by, for example, (a)forming a complex with another molecule that directly binds to thereceptor, or (b) otherwise resulting in the modification of anothercompound so that the other compound directly binds to the receptor. Anagonist may be referred to as an agonist of a particular TLR (e.g., aTLR7 and/or TLR8 agonist). The term “partial agonist” refers to acompound that produces a partial but not a full cellular response. TLR7and TLR8-related assays are known in the art (e.g., Gorden et al.,Journal of Immunology 177, pp. 8164-8170 (2006) and Zhu et al.,Molecular Immunology, vol. 45 (11), pp. 3238-3242 (2008)).

The term “antagonist” as used herein refers to a compound that competeswith an agonist or partial agonist for binding to a receptor, therebyblocking the action of an agonist or partial agonist on the receptor.More specifically, an antagonist is a compound that inhibits theactivity of TRL7 or TLR8 at the TLR7 or TLR8 receptor, respectively.“Inhibit” refers to any measurable reduction of biological activity.Thus, as used herein, “inhibit” or “inhibition” may be referred to as apercentage of a normal level of activity.

In one aspect of this invention, a method of treating or preventing acondition or disorder treatable by modulation of TLR7- and/orTLR8-mediated cellular activities in a subject comprises administeringto said subject a composition comprising a compound of the invention inan amount effective to treat or prevent the condition or disorder. Theterm “TLR7- and/or TLR8-mediated” refers to a biological or biochemicalactivity that results from TLR7- and/or TLR8 function.

Conditions and disorders that can be treated by the methods of thisinvention include, but are not limited to, cancer, immunecomplex-associated diseases, autoimmune diseases or disorders,inflammatory disorders, immunodeficiency, graft rejection,graft-versus-host disease, allergies, cardiovascular disease, fibroticdisease, asthma, infection, and sepsis.

More specifically, methods useful in the treatment of conditionsinvolving cancer (therapeutic or cancer vaccine), allergic disease(e.g., atopic dermititis, allergic rhinitis, asthma), infectious disease(prophylaxis with vaccine and anti-viral), and immunodeficiency willemploy compounds of the invention that inhibit TLR7- and/orTLR8-mediated signaling.

Alternatively, methods useful in the treatment of conditions involvingautoimmune disease, CF, sepsis, graft rejection, and GVHD generally willemploy compounds of the invention that augment TLR7- and/orTLR8-mediated signaling.

In some instances the compositions can be used to inhibit or promoteTLR7- and/or TLR8-mediated signaling in response to a TLR7 and/or TLR8ligand or signaling agonist. In other instances the compositions can beused to inhibit or promote TLR7- and/or TLR8-mediated immunostimulationin a subject.

The term “treating” as used herein, unless otherwise indicated, means atleast the mitigation of a disease or condition and includes, but is notlimited to, modulating and/or inhibiting an existing disease orcondition, and/or alleviating the disease or condition to which suchterm applies, or one or more symptoms of such disease or condition. Theterm “treatment,” as used herein, unless otherwise indicated, refers tothe act of treating as “treating” is defined immediately above.Therapeutic treatment refers to treatment initiated after observation ofsymptoms and/or a suspected exposure to a causative agent of the diseaseor condition. Generally, therapeutic treatment may reduce the severityand/or duration of symptoms associated with the disease or condition.

As used herein, “preventing” means causing the clinical symptoms of adisease or condition not to develop i.e., inhibiting the onset of adisease or condition in a subject that may be exposed to or predisposedto the disease or condition, but does not yet experience or displaysymptoms of the disease or condition. Prophylactic treatment means thata compound of the invention is administered to a subject prior toobservation of symptoms and/or a suspected exposure to a causative agentof the condition (e.g., a pathogen or carcinogen). Generally,prophylactic treatment may reduce (a) the likelihood that a subject thatreceives the treatment develops the condition and/or (b) the durationand/or severity of symptoms in the event the subject develops thecondition.

As used herein, the terms “autoimmune disease,” “autoimmune disorder”and “autoimmunity” refer to immunologically mediated acute or chronicinjury to a tissue or organ derived from the host. The terms encompassboth cellular and antibody-mediated autoimmune phenomena, as well asorgan-specific and organ-nonspecific autoimmunity. Autoimmune diseasesinclude insulin-dependent diabetes mellitus, rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis, atherosclerosis, andinflammatory bowel disease. Autoimmune diseases also include, withoutlimitation, ankylosing spondylitis, autoimmune hemolytic anemia,Bechet's syndrome, Goodpasture's syndrome, Graves' disease, GuillainBarre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia,myasthenia gravis, pernicious anemia, polyarteritis nodosa,polymyositis/dermatomyositis, primary biliary sclerosis, psoriasis,sarcoidosis, sclerosing cholangitis, Sjogren's syndrome, systemicsclerosis (scleroderma and CREST syndrome), Takayasu's arteritis,temporal arteritis, and Wegener's granulomatosis. Autoimmune diseasesalso include certain immune complex-associated diseases.

As used here in, the term “fibrotic disease” refers to diseases ordisorders involving excessive and persistent formation of scar tissueassociated with organ failure in a variety of chronic diseases affectingthe lungs, kidneys, eyes, heart, liver, and skin. Although tissueremodeling and scarring is part of the normal wound healing process,repeated injury or insult can lead to persistent and excessive scarringand, ultimately, organ failure.

Fibrotic conditions include diffuse fibrotic lung disease, chronickidney disease, including diabetic kidney disease; liver fibrosis (e.g.,chronic liver disease (CLD) caused by continuous and repeated insults tothe liver from causes such as are viral hepatitis B and C, alcoholiccirrhosis or non-alcoholic fatty liver disease (NAFLD), or primarysclerosing cholangitis (PSC), a rare disease characterized by fibrosinginflammatory destruction of the bile ducts inside and outside the liver,leading to bile stasis, liver fibrosis, and ultimately to cirrhosis, andend-stage liver disease); lung fibrosis (e.g., idiopathic pulmonaryfibrosis (IPF)); and systemic sclerosis (a degenerative disorder inwhich excessive fibrosis occurs in multiple organ systems, including theskin, blood vessels, heart, lungs, and kidneys).

Other examples include cystic fibrosis of the pancreas and lungs;injection fibrosis, which can occur as a complication of intramuscularinjections, especially in children; endomyocardial fibrosis; mediastinalfibrosis, myelofibrosis; retroperitoneal fibrosis; progressive massivefibrosis, a complication of coal workers' pneumoconiosis; nephrogenicsystemic fibrosis; and complication of certain types of surgicalimplants (e.g. occurrence in attempts at creating an artificial pancreasfor the treatment of diabetes mellitus.

As used herein, the term “cardiovascular disease” refers to diseases ordisorders of the cardiovascular system involving an inflammatorycomponent, and/or the accumulation of plaque, including withoutlimitation coronary artery disease, cerebrovascular disease, peripheralarterial disease, atherosclerosis, and arteriosclerosis.

As used herein, the terms “cancer” and, “tumor” refer to a condition inwhich abnormally replicating cells of host origin are present in adetectable amount in a subject. The cancer can be a malignant ornon-malignant cancer. Cancers or tumors include, but are not limited to,biliary tract cancer; brain cancer; breast cancer; cervical cancer;choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer;gastric (stomach) cancer; intraepithelial neoplasms; leukemias;lymphomas; liver cancer; lung cancer (e.g., small cell and non-smallcell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreaticcancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas;skin cancer; testicular cancer; thyroid cancer; as well as othercarcinomas and sarcomas. Cancers can be primary or metastatic.

As used herein, the terms “inflammatory disease” and inflammatorydisorder” refer to a condition characterized by inflammation e.g., alocalized protective reaction of tissue to irritation, injury, orinfection, characterized by pain, redness, swelling, and sometimes lossof function. Inflammatory diseases or disorders include e.g., allergy,asthma, and allergic rash.

As used herein, the term “immune complex-associated disease” refers toany disease characterized by the production and/or tissue deposition ofimmune complexes (i.e., any conjugate including an antibody and anantigen specifically bound by the antibody), including, but not limitedto systemic lupus erythematosus (SLE) and related connective tissuediseases, rheumatoid arthritis, hepatitis C- and hepatitis B-relatedimmune complex disease (e.g., cryoglobulinemia), Bechet's syndrome,autoimmune glomerulonephritides, and vasculopathy associated with thepresence of LDL/anti-LDL immune complexes.

As used herein, “immunodeficiency” refers to a disease or disorder inwhich the subject's immune system is not functioning in normal capacityor in which it would be useful to boost a subject's immune response, forexample to eliminate a tumor or cancer (e.g., tumors of the brain, lung(e.g., small cell and non-small cell), ovary, breast, prostate, colon,as well as other carcinomas and sarcomas) or an infection in a subject.The immunodeficiency can be acquired or it can be congenital.

As used herein, “graft rejection” refers to immunologically mediatedhyperacute, acute, or chronic injury to a tissue or organ derived from asource other than the host. The term thus encompasses both cellular andantibody-mediated rejection, as well as rejection of both allografts andxenografts.

“Graft-versus-host disease” (GvHD) is a reaction of donated bone marrowagainst a patient's own tissue. GVHD is seen most often in cases wherethe blood marrow donor is unrelated to the patient or when the donor isrelated to the patient but not a perfect match. There are two forms ofGVHD: an early form called acute GVHD that occurs soon after thetransplant when the white cells are on the rise and a late form calledchronic GVHD.

T_(H2)-mediated, atopic diseases include, but are not limited to, atopicdermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis,and Ommen's syndrome.

As used herein, “allergy” refers to acquired hypersensitivity to asubstance (allergen). Allergic conditions include eczema, allergicrhinitis or coryza, hay fever, asthma, urticaria (hives) and foodallergies, and other atopic conditions

As used herein, “asthma” refers to a disorder of the respiratory systemcharacterized by inflammation, narrowing of the airways and increasedreactivity of the airways to inhaled agents. Asthma is frequently,although not exclusively associated with atopic or allergic symptoms.For example, asthma can be precipitated by exposure to an allergen,exposure to cold air, respiratory infection, and exertion.

As used herein, the terms “infection” and, equivalently, “infectiousdisease” refer to a condition in which an infectious organism or agentis present in a detectable amount in the blood or in a normally steriletissue or normally sterile compartment of a subject. Infectiousorganisms and agents include viruses, bacteria, fungi, and parasites.The terms encompass both acute and chronic infections, as well assepsis.

As used herein, the term “sepsis” refers to the presence of bacteria(bacteremia) or other infectious organisms or their toxins in the blood(septicemia) or in other tissue of the body.

Further provided is a compound of the invention, or a salt thereof, foruse as a medicament in the treatment of the diseases or conditionsdescribed above in a mammal, for example, a human, suffering from suchdisease or condition. Also provided is the use of a compound of theinvention, or a salt thereof, in the preparation of a medicament for thetreatment of the diseases and conditions described above in a mammal,for example a human, suffering from such disorder.

This invention also encompasses pharmaceutical compositions containing acompound of the invention and methods of treating or preventingconditions and disorders by modulation of TLR7- and/or TLR8-mediatedcellular activities by administering a pharmaceutical compositioncomprising a compound of the invention, or a salt thereof, to a patientin need thereof.

In order to use a compound of the invention or a salt thereof for thetherapeutic treatment (including prophylactic treatment) of mammalsincluding humans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

According to this aspect of the invention there is provided apharmaceutical composition that comprises a compound of the invention,or a salt thereof, as defined hereinbefore in association with apharmaceutically acceptable diluent or carrier.

To prepare the pharmaceutical compositions according to this invention,a therapeutically or prophylactically effective amount of a compound ofthe invention or a salt thereof (alone or together with an additionaltherapeutic agent as disclosed herein) is intimately admixed, forexample, with a pharmaceutically acceptable carrier according toconventional pharmaceutical compounding techniques to produce a dose. Acarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral.Examples of suitable carriers include any and all solvents, dispersionmedia, adjuvants, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, sweeteners, stabilizers (topromote long term storage), emulsifiers, binding agents, thickeningagents, salts, preservatives, solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, flavoring agents, and miscellaneous materials such as buffersand absorbents that may be needed in order to prepare a particulartherapeutic composition. The use of such media and agents withpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with acompound of the invention, its use in the therapeutic compositions andpreparations is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions and preparations as describedherein.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, or intramusculardosing or as a suppository for rectal dosing). For example, compositionsintended for oral use may contain, for example, one or more coloring,sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, esters or partial esters derived from fatty acids and hexitolanhydrides (for example sorbitan monooleate) and condensation productsof the said partial esters with ethylene oxide such as polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening,flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above.For parenteral formulations, the carrier will usually comprise sterilewater, aqueous sodium chloride solution, 1,3-butanediol, or any othersuitable non toxic parenterally acceptable diluent or solvent. Otheringredients including those that aid dispersion may be included. Ofcourse, where sterile water is to be used and maintained as sterile, thecompositions and carriers must also be sterilized. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient that is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 micron or much less, the powder itself comprising eitheractive ingredient alone or diluted with one or more physiologicallyacceptable carriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

Compositions for transdermal administration may be in the form of thosetransdermal skin patches that are well known to those of ordinary skillin the art. Other delivery systems can include time-release, delayedrelease or sustained release delivery systems. Such systems can avoidrepeated administrations of the compounds, increasing convenience to thesubject and the physician. Many types of release delivery systems areavailable and known to those of ordinary skill in the art. They includepolymer base systems such as poly(lactide-glycolide), copolyoxalates,polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyricacid, and polyanhydrides. Microcapsules of the foregoing polymerscontaining drugs are described in, for example, U.S. Pat. No. 5,075,109.Delivery systems also include non-polymer systems that are: lipidsincluding sterols such as cholesterol, cholesterol esters and fattyacids or neutral fats such as mono-di- and tri-glycerides; hydrogelrelease systems; silastic systems; peptide based systems; wax coatings;compressed tablets using conventional binders and excipients; partiallyfused implants; and the like. Specific examples include, but are notlimited to: (a) erosional systems in which an agent of the invention iscontained in a form within a matrix such as those described in U.S. Pat.Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusional systems inwhich an active component permeates at a controlled rate from a polymersuch as described in U.S. Pat. Nos. 3,854,480, 5,133,974 and 5,407,686.In addition, pump-based hardware delivery systems can be used, some ofwhich are adapted for implantation.

Compositions may be administered in the form of a solution, e.g., wateror isotonic saline, buffered or unbuffered, or as a suspension, forintranasal administration as drops or as a spray. Preferably, suchsolutions or suspensions are isotonic relative to nasal secretions andof about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatibleand include, simply by way of example, phosphate buffers. For example, arepresentative nasal decongestant is described as being buffered to a pHof about 6.2 (Remington's Pharmaceutical Sciences, Ed. By Arthur Osol,p. 1445 (1980)). Of course, the ordinary artisan can readily determine asuitable saline content and pH for an innocuous aqueous carrier fornasal administration.

Other, non-limiting examples of intranasal dosage forms containing thecomposition include nasal gels, creams, pastes or ointments with aviscosity of, e.g., from about 10 to about 3000 cps, or from about 2500to 6500 cps, or greater, which may provide a more sustained contact withthe nasal mucosal surfaces. Such carrier viscous formulations may bebased upon, simply by way of example, polymeric carriers such asalkylcelluloses and/or other biocompatible carriers of high viscositywell known to the art (see e.g., Remington's, cited supra). The carriercontaining the composition may also be soaked into a fabric material,such as gauze, that can be applied to the nasal mucosal surfaces toallow for active substances in the isolated fraction to penetrate to themucosa.

Other ingredients, such as art known preservatives, colorants,lubricating or viscous mineral or vegetable oils, perfumes, natural orsynthetic plant extracts such as aromatic oils, and humectants andviscosity enhancers such as, e.g., glycerol, can also be included toprovide additional viscosity, moisture retention and a pleasant textureand odor for the formulation.

Further, for nasal administration of solutions or suspensions of thecomposition, various devices are available in the art for the generationof drops, droplets and sprays. For example, solutions comprising theisolated fraction can be administered into the nasal passages by meansof a simple dropper (or pipet) that includes a glass, plastic or metaldispensing tube from which the contents are expelled drop by drop bymeans of air pressure provided by a manually powered pump, e.g., aflexible rubber bulb, attached to one end. Fine droplets and sprays canbe provided by a manual or electrically powered intranasal pumpdispenser or squeeze bottle as well known to the art, e.g., that isdesigned to blow a mixture of air and fine droplets into the nasalpassages.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. However, an effectivedosage is in the range of about 0.001 to about 100 mg per kg body weightper day, for example, about 0.05 to about 35 mg/kg/day, in single ordivided doses. For example a dosage is about 0.0005 to about 2.5 g/day.For example, a dosage is about 0.0005 to about 1 g/day in single ordivided dosages. In some instances, dosage levels below the lower limitof the aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffect, provided that such larger doses are first divided into severalsmall doses for administration throughout the day.

For further information on routes of administration and dosage regimes,see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry(Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, whichis specifically incorporated herein by reference.

The size of the dose for therapeutic or prophylactic purposes of acompound of the invention will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. It will be understood that the specific dosage level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors including the activity of the specificcompound of the invention, the species, age, body weight, generalhealth, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition, but can nevertheless be routinely determined byone skilled in the art.

A compound of the invention or salt thereof, is in some aspectsadministered to a subject in combination (e.g., in the same formulationor in separate formulations) with another therapeutic agent(“combination therapy”). The compound of the invention is administeredin admixture with another therapeutic agent or is administered in aseparate formulation. When administered in separate formulations, acompound of the invention and another therapeutic agent is administeredsubstantially simultaneously or sequentially. In one aspect, a compoundof the invention is administered to a subject in combination withanother therapeutic agent for treating a condition or disease. In oneaspect, a compound of the invention is administered to a subject incombination with another therapeutic agent for preventing a condition ordisease. In one aspect, a compound of the invention is administered to asubject in combination with a vaccine for preventing a condition ordisease. In one aspect, a compound of the invention is administered to asubject in combination with an infectious disease vaccine. In oneaspect, a compound of the invention is administered to a subject incombination with a cancer vaccine.

A compound of the invention may be useful as a vaccine adjuvant for usein conjunction with any material that raises either humoral and/or cellmediated immune response, such as, for example, live viral, bacterial,or parasitic immunogens; inactivated viral, tumor-derived, protozoal,organism-derived, fungal, or bacterial immunogens, toxoids, toxins;self-antigens; polysaccharides; proteins; glycoproteins; peptides;cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins;peptides; and the like, for use in connection with, for example, BCG,cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C,influenza A, influenza B, parainfluenza, polio, rabies, measles, mumps,rubella, yellow fever, tetanus, diphtheria, hemophilus influenza b,tuberculosis, meningococcal and pneumococcal vaccines, adenovirus, HIV,chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague,HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratorysyncytial virus, rotavirus, papilloma virus, yellow fever, andAlzheimer's Disease.

A compound of the invention may also be helpful in individuals havingcompromised immune function. For example, a compound of the inventionmay be used for treating or preventing the opportunistic infections andtumors that occur after suppression of cell mediated immunity in, forexample, transplant patients, cancer patients and HIV patients.

Such combination treatment may involve, in addition to a compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumor agents: (i) antiproliferative/anti-neoplastic drugs andcombinations thereof; (ii) cytostatic agents; (iii) agents which inhibitcancer cell invasion; (iv) inhibitors of growth factor function; (v)antiangiogenic agents; (vi) vascular damaging agents; (vii) antisensetherapies; (viii) gene therapy approaches; (ix) interferon; and (x)immunotherapy approaches.

Therapeutic agents for treating or preventing respiratory diseases whichmay be administered in combination with a compound of the invention in asubject method include, but are not limited to beta adrenergics whichinclude bronchodilators including albuterol, isoproterenol sulfate,metaproterenol sulfate, terbutaline sulfate, pirbuterol acetate andsahneterol formotorol; steroids including beclomethasone dipropionate,flunisolide, fluticasone, budesonide and triamcinolone acetonide.Anti-inflammatory drugs used in connection with the treatment orpreventing of respiratory diseases include steroids such asbeclomethasone dipropionate, triamcinolone acetonide, flunisolide andfluticasone. Other anti-inflammatory drugs include cromoglycates such ascromolyn sodium. Other respiratory drugs which would qualify asbronchodilators include anticholenergics including ipratropium bromide.Anti-histamines include, but are not limited to, diphenhydramine,carbinoxamine, clemastine, dimenhydrinate, pryilamine, tripelennamine,chlorpheniramine, brompheniramine, hydroxyzine, cyclizine, meclizine,chlorcyclizine, promethazine, doxylamine, loratadine, and terfenadine.Particular anti-histamines include rhinolast (Astelin®), claratyne(Claritin®), claratyne D (Claritin D®), telfast (Allegra®), Zyrtec®, andbeconase.

In some embodiments, a compound of the invention is administered as acombination therapy with interferon-gamma (IFN-gamma), a corticosteroidsuch as prednisone, prednisolone, methyl prednisolone, hydrocortisone,cortisone, dexamethasone, betamethasone, etc., or a combination thereof,for the treatment or preventing of interstitial lung disease, e.g.,idiopathic pulmonary fibrosis.

In some embodiments, a compound of the invention is administered incombination therapy with a known therapeutic agent used in the treatmentof cystic fibrosis (“CF”). Therapeutic agents used in the treatment ofCF include, but are not limited to, antibiotics; anti-inflammatoryagents; DNAse (e.g., recombinant human DNAse; pulmozyme; dornase alfa);mucolytic agents (e.g., N-acetylcysteine; Mucomyst™; Mucosil™);decongestants; bronchodilators (e.g., theophylline; ipatropium bromide);and the like.

In some embodiments, a compound of the invention is administeredprophylatically for the prevention of cardiovascular disease, e.g.,atherosclerosis.

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment or prevention ofthe diseases described above is provided.

In one embodiment, the kit comprises a container comprising acomposition of the invention, or pharmaceutically acceptable saltthereof. In one embodiment, the invention provides a kit for treating orpreventing a TLR7- and/or TLR8-mediated disorder. In another embodiment,the invention provides a kit for a condition or disorder treatable byselective modulation of the immune system in a subject. The kit mayfurther comprise a label or package insert on or associated with thecontainer. Suitable containers include, for example, bottles, vials,syringes, blister pack, etc. The container may be formed from a varietyof materials such as glass or plastic. The container holds a compound ofthe invention or a pharmaceutical formulation thereof in an amounteffective for treating or preventing the condition, and may have asterile access port (for example, the container may be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). The label or package insert indicates that thecomposition is used for treating or preventing the condition of choice.In one embodiment, the label or package inserts indicates that thecomposition comprising a compound of the invention can be used, forexample, to treat or prevent a disorder treatable by modulation of TLR7-and/or TLR8-mediated cellular activities. The label or package insertmay also indicate that the composition can be used to treat or preventother disorders. Alternatively, or additionally, the kit may furthercomprise a second container comprising a pharmaceutically acceptablebuffer, such as bacteriostatic water for injection (BWFI),phosphate-buffered saline, Ringer's solution and dextrose solution. Itmay further include other materials desirable from a commercial and userstandpoint, including other buffers, diluents, filters, needles, andsyringes.

The kit may further comprise directions for the administration of thecompound of the invention and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of the invention and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of the invention, such as tablets or capsules.Such a kit includes, for example, a number of unit dosages. Such kitscan include a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, the kit may comprise (a) a first containerwith a compound of the invention contained therein; and optionally (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound which may be effective in treating or preventing acondition or disorder by selective modulation of TLR7- and/orTLR8-mediated cellular activities. Alternatively, or additionally, thekit may further comprise a third container comprising a pharmaceuticallyacceptable buffer, such as bacteriostatic water for injection (BWFI),phosphate-buffered saline, Ringer's solution and dextrose solution. Itmay further include other materials desirable from a commercial and userstandpoint, including other buffers, diluents, filters, needles, andsyringes.

In certain other embodiments wherein the kit comprises a pharmaceuticalformulation of a compound of the invention and a second formulationcomprising a second therapeutic agent, the kit may comprise a containerfor containing the separate formulations, such as a divided bottle or adivided foil packet; however, the separate compositions may also becontained within a single, undivided container. Typically, the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare administered in different dosage forms (e.g., oral and parenteral),are administered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

Activity of the compounds can be assessed according to proceduresdescribed in, e.g., Gorden et al., Journal of Immunology 177, pp.8164-8170 (2006) and Zhu et al., Molecular Immunology, vol. 45 (11), pp.3238-3242 (2008).

MC₅₀ values for TLR8 activity are, for example, as shown below:

Compound Structure TLR8 (MC₅₀) 143

 45 nM 154

116 nM 106

 10 nM 127

 4 nM 124

104 nM 190

196 nM

MC₅₀ values for TLR7 activity are, for example, as shown below:

Compound Structure TLR7 (MC₅₀) 178

767 nM 135

744 nM

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that chemicalreactions described may be readily adapted to prepare a number of othercompounds of the invention, and alternative methods for preparing thecompounds of this invention are also deemed to be within the scope ofthis invention. For example, the synthesis of non-exemplified compoundsaccording to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,Acros, TCI, Alfa Aesar or Maybridge, and were used without furtherpurification unless otherwise indicated.

In the examples described below, the term “Example ###” refers to“Compound ###”. For example, Example 101 is directed to Compound 101and/or synthetic procedures relating to Compound 113.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heated dried.

Microwave reactions were performed on the Biotage Initiator system.

Column chromatography was done on a Biotage system or Isolute Flash SiSPE column (manufacturer: Biotage AB) having a silica gel column or on asilica SepPak cartridge (Waters). ¹H and ¹⁹F NMR spectra were recordedon a Varian instrument operating at 400 MHz and 376 MHz, respectively.¹H-NMR spectra were obtained as CDCl₃ or d₆-DMSO solutions (reported inppm), using chloroform (7.26 ppm) or tetramethylsilane (0 ppm) as thereference standards. When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),q (quartet), br (broadened), dd (doublet of doublets), dt (double oftriplets), m (multiplet).

Example 1 Synthetic Procedures

1. Synthesis of Compound 15

In a three-necked flask provided with a mechanical stirrer, droppingfunnel, and thermometer, surrounded by an ice-salt bath, are placed 400mL of acetic anhydride and 50 g (0.23 mole) of4-bromo-1-methyl-2-nitrobenzene. To this solution is added slowly withstirring 54 mL of concentrated sulfuric acid. When the mixture hascooled to 0° C., a solution of 64 g of chromium trioxide in 360 mL ofacetic anhydride is added slowly with stirring; at such a rate that thetemperature does not exceed 10 and stirring is continued for 2 hours at5-10° C. in an ice-water bath after the addition is complete. Thecontents of the flask are poured into the mixture of ice and water. Thesolid was filtered and washed with water until the washings arecolorless. The product is suspended in 300 mL of 2% aqueous sodiumcarbonate solution and stirred. After thorough mixing, the solid wasfiltered and washed with water and dried.

A suspension of the diacetate in a mixture of 272 mL of concentratedhydrochloric acid, 250 mL of water, and 80 mL of ethanol was stirred andrefluxed for 45 minutes. The mixture was then cooled to RT and the solidwas filtered and washed with water. The crude product is purified bycolumn (22 g, 42%).

2. Synthesis of Compound 16

A mixture of the aldehyde (0.73 g, 3.17 mmol) and the ylide (1.42 g,3.65 mmol) in toluene (8 mL) was gently refluxed for 2.5 hrs. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure to give the crude material that was used directlywithout further purification.

3. Synthesis of Compounds 17 and 17B

To a solution of the crude nitrile in AcOH (25 ml) was added iron (1.15g, 20.61 mmol) at a room temperature. The resulting mixture was heatedat 85° C. for 4 h. The reaction mixture was cooled to room temperatureand diluted with CH₂Cl₂ (8 mL). The resulting mixture was filtered, thesolids were washed with CH₂Cl₂. The filtrate was concentrated underreduced pressure to give viscous oil. To the crude material was addedCH₂Cl₂ (8 mL). aq. Na₂CO₃ followed by water was slowly added withstirring until its pH=9-10. The mixture was filtered off and washed withCH₂Cl₂. The organic layer was separated. The aqueous layer was extractedwith CH₂Cl₂. The organic layer was separated. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄, the mixture was concentrated under reducedpressure to give the crude material that was purified by silica gelflash column chromatography to afford 0.329 g (33% for two steps) of thedesired product was obtained based on ¹H-NMR.

4. Synthesis of Compound 18

To the benzazepine (2.34 g, 7.57 mmol) in DCM (25 mL) was added Boc₂O(2.06 g, 9.46 mmol) at room temperature. The reaction mixture wasstirred for 20 hrs. The resulting mixture was consecutively washed withssaturated aq. NaHCO₃ and brine. The organic layer was separated anddried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the crude product that was purified by silica gel flash columnchromatography (10% EtOAc in hexanes) to afford 1.64 g (52.9%) of thedesired product.

5. Synthesis of Species Example 101

(1E,4E)-2-amino-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine

A solution of 4-bromo-2-nitrotoluene (100 g, 463 mmol), pyrrolidine(46.2 mL, 565 mmol), and N,N-dimethylformamide dimethylacetal (75.6 mL,565 mmol) was refluxed for 4 hours at

110° C. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to give the crude(E)-1-(4-bromo-2-nitrostyryl)pyrrolidine that was used directly withoutfurther purification.

Step B: Preparation of 4-bromo-2-nitrobenzaldehyde

To a solution of sodium periodate (298 g, 1.40 mol) in THF—H₂O (4 L,1:1) at 0° C. was added (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine (138 g,464 mmol). The mixture was stirred for 15 h and then filtered to removesolid precipitates. The aqueous layer from the filtrate was separatedand extracted with EtOAc (4×200 mL). The combined organic layers werewashed with H₂O (2×200 mL), dried over MgSO₄, filtered, and concentratedunder reduced pressure to give the crude product that was purified bysilica gel flash column chromatography (5% EtOAc in hexanes) to afford91 g (86%) of 4-bromo-2-nitrobenzaldehyde.

Step C: Preparation of3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-carbaldehyde

To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol),4-(pyrrolidine-1-carbonyl)phenylboronic acid (21.2 g, 96.7 mmol), andPd(PPh₃)₄ (508 mg, 0.440 mmol) in toluene (200 mL) was added EtOH (40mL) followed by Na₂CO₃ (70.0 mL, 140 mmol, 2 M aq solution) at roomtemperature. The resulting mixture was heated at 100° C. for 18 h. Thereaction mixture was cooled to room temperature and the organic layerwas separated. The aqueous layer was extracted with EtOAc (300 mL). Thecombined organic layers were washed with brine (500 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure to give thecrude material that was combined with another batch of the crudematerial obtained from an additional run in the same reaction scale. Thecombined crude material was purified by silica gel flash columnchromatography (CH₂Cl₂ to 1% MeOH in CH₂Cl₂) to afford 51 g (90%) of3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-carbaldehyde.

Step D: Preparation of (E)-ethyl2-(cyanomethyl)-3-(3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-yl)acrylate

A mixture of 3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-carbaldehyde(20.0 g, 61.7 mmol) and α-cyanomethylcarboethoxyethylidenetriphenylphosphorane (26.3 g, 67.8 mmol) in toluene (200 mL) was gentlyrefluxed for 2.5 h. The reaction mixture was cooled to room temperatureand concentrated under reduced pressure to give the crude (E)-ethyl2-(cyanomethyl)-3-(3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-yl)acrylatethat was used directly without further purification.

Step E: Preparation of (1E,4E)-ethyl2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate

To a solution of the crude (E)-ethyl2-(cyanomethyl)-3-(3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-yl)acrylatein AcOH (650 mL) was added iron (29.1 g, 521 mmol) at room temperature.The resulting mixture was heated at 85° C. for 4 h. The reaction mixturewas cooled to room temperature and diluted with CH₂Cl₂ (250 mL). Thesolids were filtered off and washed with CH₂Cl₂ (200 mL). The filtratewas concentrated under reduced pressure to give the crude material thatwas diluted with CH₂Cl₂ (250 mL) again. To this mixture was slowly addedsat'd aq Na₂CO₃ (˜330 mL) with vigorous stirring until it became basic(pH ˜9-10). The resulting mixture was filtered off and washed withCH₂Cl₂ (˜250 mL). The aqueous layer was separated and extracted withCH₂Cl₂ (2×150 mL). The combined organic layers were washed with brine,dried over MgSO₄, and filtered to give the crude material that wasdiluted with EtOAc (70 mL). The mixture was kept for 16 h at roomtemperature. The suspension was filtered. The solids filtered off werewashed with EtOAc (100 mL) to give the crude product that was washedwith a small amount of CH₂Cl₂ to afford 20 g (62% based on 95% purity)of (1E,4E)-ethyl2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate.

Step F: Preparation of (1E,4E)-ethyl2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate

To a mixture of (1E,4E)-ethyl2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate(9.60 g, 23.8 mmol) in CH₂Cl₂ (100 mL) was added Boc₂O (5.97 mg, 27.4mmol) at room temperature. The reaction mixture was stirred for 3 days.The resulting mixture was washed with sat'd aq NaHCO₃ and brine. Theorganic layer was separated and dried over MgSO₄, filtered, andconcentrated under reduced pressure to give 12.7 g of the crude(1E,4E)-ethyl2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylatethat was used directly without further purification. MS APCI(+) m/z 504(M+1) detected.

Step G: Preparation of(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid

To a solution of (1E,4E)-ethyl2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate(12.0 g, 23.8 mmol) in THF-EtOH (60 mL/60 mL) was added 4 N aq. LiOH(23.8 mL, 95.3 mmol) at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 21 h. Additional 6 mL of 4 N aq LiOH wasadded twice after 21 h and 24 h. After stirring for additional 6 h, theresulting mixture was concentrated under reduced pressure to give thecrude material that was diluted with water (50 mL) and acidified to a pHof ˜3.5 with 1 N aq phosphoric acid (˜450 mL). ˜250 mL of CH₂Cl₂ wasadded during acidification to extract the crude product out of thesticky suspension. The solids formed during acidification were filteredoff using a glass filter packed with Celite. The aqueous layer wasseparated and extracted with CH₂Cl₂ (3×100 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressures to give 10.2 g (90%) of the crude(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid that was used directly without further purification. MS APCI(+) m/z476 (M+1) detected.

Step H: Preparation of tert-butyl(1E,4E)-4-(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate

A mixture of(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid (200 mg, 0.42 mmol), HOBt (114 mg, 0.84 mmol), and EDCI (161 mg,0.84 mmol) in DMF (5 mL) was stirred for 1 h at room temperature. Tothis mixture was added triethylamine (0.12 mL, 0.84 mmol) andpropan-1-amine (0.043 mL, 0.53 mmol) at room temperature. The resultingsolution was stirred for additional 2 h. The reaction mixture wasdiluted with EtOAc (5 mL) and washed with sat'd aq NH₄Cl. The aqueouslayer was seperated and extracted with EtOAc (3×5 mL). The combinedorganic layers were washed with brine (5 mL), sat'd aq NaHCO₃ (5 mL),and brine (5 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure to give the crude tert-butyl(1E,4E)-4-(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamatethat was used directly without further purification.

Step I: Preparation of(1E,4E)-2-amino-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

To a solution of tert-butyl(1E,4E)-4-(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate(450 mg, 0.87 mmol) in CH₂Cl₂ (5 mL) was added 2,2,2-trifluoroaceticacid (1.36 mL, 17.4 mmol) at 0° C. The reaction mixture was warmed toroom temperature and stirred for 2 h. The reaction mixture wasconcentrated under reduced pressure to give the crude material that wasdiluted with CH₂Cl₂ (10 mL) and sat'd aq NaHCO₃ (15 mL) again. Theresulting mixture was stirred for 30 min at room temperature. Theaqueous layer was separated and extracted with CH₂Cl₂ (1×10 mL). Thecombined organic layers were washed with sat'd aq NaHCO₃ (2×10 mL) andbrine (1×10 mL), dried over MgSO₄, filtered, and concentrated underreduced pressure to give the crude material again that was purified bysilica gel flash column chromatography (1 to 5% MeOH in CH₂Cl₂,gradient) to yield 27 mg (7%) of(1E,4E)-2-amino-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide.MS APCI(+) m/z 417 (M+1) detected; ¹H-NMR (400 MHz, d₆-DMSO) δ 8.27 (t,1H), 7.75 (d, 2H), 7.62 (d, 2H), 7.50 (d, 2H), 7.41 (d, 2H), 3.43-3.51(m, 4H), 3.18 (q, 2H), 2.99 (s, 2H), 1.81-1.90 (m, 4H), 1.48-1.58 (m,2H), 0.90 (t, 3H).

The following examples 102 and 103 were prepared by the procedures asdescribed in Example 101 (Step H and I) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and N-propylbutan-2-amine or diisobutylamine.

Example 102

(1E,4E)-2-amino-N-sec-butyl-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

MS APCI(+) m/z 473 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.67 (d,2H), 7.60 (d, 2H), 7.52 (s, 1H), 7.36 (d, 1H), 7.32 (dd, 1H), 6.80 (s,1H), 4.21-4.26 (m, 1H), 3.67 (t, 2H), 3.50 (t, 2H), 3.37-3.44 (m, 1H),2.95-3.10 (m, 1H), 2.92 (d, 1H), 2.79 (d, 1H), 1.88-2.00 (m, 4H),1.50-1.77 (m, 4H), 1.29 (d, 3H), 0.94 (t, 3H), 0.86 (br s, 3H).

Example 103

(1E,4E)-2-amino-N,N-diisobutyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

MS APCI(+) m/z 487 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.68 (d,2H), 7.60 (d, 2H), 7.51 (s, 1H), 7.39 (d, 1H), 7.31 (dd, 1H), 6.82 (s,1H), 3.67 (t, 2H), 3.51 (t, 2H), 3.22-3.52 (br s, 4H), 2.81 (s, 2H),1.88-2.14 (m, 6H), 0.90 (br s, 12H).

Example 104

(1E,4E)-2-amino-N-(2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine

To a solution of 1-(propylamino)propan-2-ol (8.00 g, 68.3 mmol),tert-butylchlorodimethylsilane (10.9 g, 72.4 mmol), and catalytic amountof DMAP in CH₂Cl₂ (68 mL) at 0° C. was added dropwise TEA (9.61 ml, 68.3mmol). The reaction mixture was warmed to room temperature and stirredfor 20 h. Additional 1 mL of TEA was added and stirred for additional 20h. Water (60 mL) was added. The layers were separated. The aqueous layerwas extracted with EtOAc (1×). The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated under reducedpressure to give the crude material that was filtered again to affordquantitatively 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-aminethat was used directly without further purification.

Step B: Preparation of(1E,4E)-2-amino-N-(2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedures as described inExample 101 (Steps H and I) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MSAPCI(+) m/z 475 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.67 (d, 2H),7.60 (d, 2H), 7.49 (s, 1H), 7.29-7.34 (m, 2H), 6.87 (s, 1H), 4.11 (br s,1H), 3.48-3.71 (m, 7H), 3.29 (dd, 1H), 2.93 (d, 1H), 2.80 (d, 1H),1.86-2.01 (m, 4H), 1.61-1.74 (m, 2H), 1.22 (d, 3H), 0.91 (t, 3H).

The following examples 105 and 106 were prepared by chiral separation ofexample 104 (column: Chiral Tech IA semi-prep column (10 mm×250 mm);flow rate: 4.8 mL/min; UV: 220 nm, solvents: EtOH-isooctane (50:50)).Their absolute configuration was arbitrarily assigned.

Example 105

(1E,4E)-2-amino-N-((S)-2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

Retention time 10.08 min.

Example 106

(1E,4E)-2-amino-N-((R)-2-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

Retention time 9.09 min.

Example 107

(1E,4E)-2-amino-N-(2-hydroxyethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedures as described inExample 104 using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-1-amine that wasprepared by the procedure as described in Example 104 (Step A) using2-(propylamino)ethanol. MS APCI (+) m/z 461 (M+1) detected; 1H-NMR (400MHz, CDCl₃) δ 7.68 (d, 2H), 7.60 (d, 2H), 7.49 (s, 1H), 7.29-7.35 (m,2H), 6.88 (s, 1H), 3.84 (s, 2H), 3.67 (t, 4H), 3.50 (t, 4H), 2.84 (s,2H), 1.88-2.00 (m, 4H), 1.66-1.72 (m, 2H), 0.93 (t, 3H).

Example 109

(1E,4E)-2-amino-N-(3-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine

The title compound was prepared by the procedure as described in Example104 (Step A) using 3-(propylamino)propan-1-ol.

Step B: Preparation of tert-butyl(1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate

The title compound was prepared by the procedure as described in Example101 (Step H) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MSAPCI(+) m/z 689 detected.

Step C: Preparation of(1E,4E)-2-amino-N-(3-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

To a mixture of tert-butyl(1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate(459 mg, 0.37 mmol) in CH₂Cl₂ (4 mL) at 0° C. was added TFA (1.00 mL).The resulting mixture was warmed to room temperature and stirred for 1h. The reaction mixture was concentrated under reduced pressure to givethe crude material that was azeotroped with toluene-EtOH (3 mL/1 mL)twice. The crude material was dried under reduced pressure for 30 min.The crude material was dissolved into CH₂Cl₂ (˜3 mL) again and treatedwith NH₃ in MeOH (0.30 mL, 2.1 mmol, 7 N solution in MeOH) at roomtemperature. The resulting mixture was stirred for 1 h. The resultingmixture was concentrated under reduced pressure to give the crudematerial that was purified by silica gel flash column chromatography (3to 7% MeOH in CH₂Cl₂, gradient) to afford 105 mg (59%) of(1E,4E)-2-amino-N-(3-hydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide.MS APCI (+) m/z 475 detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.67 (d, 2H),7.60 (d, 2H), 7.51 (br s, 1H), 7.30-7.37 (m, 2H), 6.88 (s, 1H),3.60-3.69 (m, 6H), 3.48-3.52 (m, 4H), 2.83 (s, 2H), 1.82-2.00 (m, 6H),1.68-1.74 (m, 2H), 0.93 (t, 3H).

Example 110

(1E,4E)-2-amino-N-(2,3-dihydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of 2,2-dimethyl-1,3-dioxolane-4-carbaldehyde

A solution of anhydrous DMSO (3.41 mL, 48 mmol) in CH₂Cl₂ (5 mL) wasadded dropwise to a stirred solution of oxalyl chloride (1.92 mL, 22mmol) in CH₂Cl₂ (50 mL) at −60° C. To this mixture was added a solutionof (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (2.48 mL, 20 mmol) inCH₂Cl₂ (10 mL). The resulting mixture was stirred for 15 min at −60° C.TEA (13.9 mL, 100 mmol) was added dropwise. The reaction mixture wasthen warmed to room temperature. Water (50 mL) and CH₂Cl₂ (50 mL) wereadded. The organic layer was separated and washed with water (25 mL).The aqueous layer was extracted with CH₂Cl₂ (3×50 mL). The organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to afford the crude 2,2-dimethyl-1,3-dioxolane-4-carbaldehydethat was used directly without further purification.

Step B: Preparation ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propan-1-amine

To a solution of propylamine (0.72 mL, 7.7 mmol) and2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (1.0 g, 7.7 mmol) in1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (2.28g, 10.8 mmol). The mixture was stirred for 1.5 h at room temperature.The reaction mixture was then quenched with sat'd aq NaHCO₃ andextracted with EtOAc. The organic layer was dried with MgSO₄, filtered,and concentrated under reduced pressure to give the crude material thatwas purified by silica gel flash column chromatography (CH₂Cl₂ to 10%MeOH in CH₂Cl₂, gradient) to afford 1.26 g (73%) ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propan-1-amine.

Step C: Preparation of(1E,4E)-2-amino-N-(2,3-dihydroxypropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedures as described inExample 101 (Step H and I) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propan-1-amine.

Example 112

(4-((1E,4E)-2-amino-4-((3R,4R)-3,4-dihydroxypyrrolidine-1-carbonyl)-3H-benzo[b]azepin-8-yl)phenyl)(pyrrolidin-1-yl)methanoneStep A: Preparation of(3R,4R)-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine

To a solution of (3R,4R)-1-benzylpyrrolidine-3,4-diol (7.00 g, 36.2mmol) and 1H-imidazole (10.9 g, 159 mmol) in DMF (35 mL) at 0° C. wasadded tert-butylchlorodimethylsilane (12.0 g, 79.7 mmol). After stirringfor 10 min, the mixture was heated to 60° C. for 4 hours. After coolingto room temperature, the reaction was diluted with H₂O (25 ml) andextracted with pet ether (3×20 mL). The combined organic layers werewashed with H₂O (2×20 mL) and sat'd aq NaHCO₃ (2×20 mL), dried overMgSO₄, filtered and concentrated under reduced pressure to give thecrude that was filtered through a silica plug (1% MeOH in CH₂Cl₂) toafford 13.4 g (88%) of(3R,4R)-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine.

Step B: Preparation of(3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine

A mixture of(3R,4R)-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine (13.4 g,31.8 mmol) and Pd(OH)₂/C (2.23 g, 3.18 mmol, 20%) in MeOH (134 mL) wasstirred for 20 h under H₂ atmosphere (balloon). The reaction mixture wasfiltered through a Celite plug and concentrated under reduced pressureto afford 10.5 g (91%) of the crude(3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine that was useddirectly without further purification.

Step C: Preparation of(4-((1E,4E)-2-amino-4-((3R,4R)-3,4-dihydroxypyrrolidine-1-carbonyl)-3H-benzo[b]azepine-8-yl)phenyl)(pyrrolidin-1-yl)methanone

The title compound was prepared by the procedures as described inExample 101 (Steps H and I) with conc. HCl instead of TFA using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and (3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidin.

The following examples 115 and 117 were prepared by the procedures asdescribed in Example 101 (Steps H and I) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and the appropriate amines (2-methyl-1-(propylamino)propan-2-ol wasprepared by the procedure reported in J. Am. Chem. Soc. 1939, 61, 3562)or the hydroxylamine.

Example 115

(1E,4E)-2-amino-N-cyclopropyl-N-(piperidin-4-yl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

m/z (APCI-pos) M+1=481.2.

Example 117

(1E,4E)-2-amino-N-(2-hydroxy-2-methylpropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

m/z (APCI-pos) M+1=489.2.

The following examples 119, 120, 121, and 122 were prepared by theprocedures as described in Example 101 (Step H and I) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and the appropriate amines.

Example 119

(1E,4E)-2-amino-N-(2-methoxyethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 475 (M+1) detected; 1H-NMR (400 MHz, CDCl₃) δ 7.67 (d,2H), 7.60 (d, 2H), 7.52 (s, 1H), 7.37 (d, 1H), 7.31-7.33 (m, 1H), 6.91(s, 1H), 3.68 (t, 4H), 3.58 (br s, 2H), 3.50 (t, 4H), 3.37 (s, 3H), 2.85(s, 2H), 1.88-2.01 (m, 4H), 1.62-1.70 (m, 2H), 0.93 (t, 3H).

Example 120

(1E,4E)-2-amino-N,N-bis(2-methoxyethyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 491 (M+1) detected; 1H-NMR (400 MHz, CDCl₃) δ 7.67 (d,2H), 7.60 (d, 2H), 7.50 (s, 1H), 7.38 (d, 1H), 7.30 (dd, 1H), 6.99 (s,1H), 3.76 (br s, 4H), 3.67 (t, 2H), 3.60 (br s, 4H), 3.50 (t, 2H), 3.37(s, 6H), 2.83 (s, 2H), 1.88-2.00 (m, 4H).

Example 121

(4-((1E,4E)-2-amino-4-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepin-8-yl)phenyl)(pyrrolidin-1-yl)methanone

MS APCI (+) m/z 429 (M+1) detected; 1H-NMR (400 MHz, CDCl₃) δ 7.68 (d,2H), 7.60 (d, 2H), 7.51 (s, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.06 (s,1H), 3.74 (br s, 2H), 3.67 (br s, 2H), 3.60 (br s, 2H), 3.50 (br s, 2H),2.88 (s, 2H), 1.90-1.97 (m, 8H).

Example 122

(4-((1E,4E)-2-amino-4-(piperidine-1-carbonyl)-3H-benzo[b]azepin-8-yl)phenyl)(pyrrolidin-1-yl)methanone

MS APCI (+) m/z 443 (M+1) detected; 1H-NMR (400 MHz, CDCl₃) δ 7.68 (d,1H), 7.62-7.67 (m, 4H), 7.56 (dd, 1H), 7.45 (d, 1H), 6.93 (s, 1H),3.66-3.70 (m, 6H), 3.49 (t, 2H), 3.23 (s, 2H), 1.90-2.01 (m, 4H), 1.74(m, 2H), 1.67 (m, 4H).

Example 124

(1E,4E)-2-amino-8-(4-(dimethylcarbamoyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of (E)-ethyl3-(4-bromo-2-nitrophenyl)-2-(cyanomethyl)acrylate

A mixture of 4-bromo-2-nitrobenzaldehyde (30.0 g, 130.4 mmol) andα-cyanomethylcarboethoxyethylidene triphenylphosphorane (54.4 g, 140mmol) in toluene (480 mL) was heated for 3 h at 110° C. The reactionmixture was cooled to room temperature. The solids were filtered off andwashed with toluene (50 mL). The filtrate was concentrated again underreduced pressure to give the crude material that was triturated inheptane (100 mL). The precipitates were filtered off and washed withheptane (20 mL). After drying under reduced pressure the crude productwas taken into MeOH (250 mL) at room temperature and swirled severaltimes during 30 min. The mixture was kept at freezer for 16 h, filtered,and rinsed with pre-chilled MeOH (2×20 mL) to afford 36.6 g (83%) of(E)-ethyl 3-(4-bromo-2-nitrophenyl)-2-(cyanomethyl)acrylate.

Step B: Preparation of (1E,4E)-ethyl2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate

A mixture of (E)-ethyl 3-(4-bromo-2-nitrophenyl)-2-(cyanomethyl)acrylate(20.0 g, 59.0 mmol) in AcOH (380 mL) was heated to 80° C. To thismixture iron (19.8 g, 354 mmol) was added portionwise over 1 h keepingthe internal temperature below 100° C. After completion of addition ofiron, the reaction mixture was heated for additional 2.5 h at 80-85° C.until the starting material disappeared on HPLC. The reaction mixturewas cooled to room temperature and filtered through a GF/F filter packedwith Celite rinsing with AcOH. The filtrate was concentrated underreduced pressure to give the crude material which was diluted with water(150 mL). The aqueous mixture was treated with sat'd NaHCO₃ (200 mL)until it became basic (pH>8). To the suspension was added additionalEtOAc (350 mL). The whole mixture was filtered through a filter packedwith Celite. The solids filtered off were diluted with EtOAc (300 mL),stirred for 15 min, and filtered again. This process with the solidsfiltered off was repeated one more time. All of the organic layers werecombined and washed with sat'd aq NaHCO₃ (300 mL) followed by brine (300mL), dried over MgSO₄, filtered while rinsing with EtOAc, andconcentrated under reduced pressure to give the crude material that wastriturated with ether (100 mL) to afford 16.5 g (91%) of (1E,4E)-ethyl2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate.

Step C: Preparation of (1E,4E)-ethyl8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate

To a suspension of (1E,4E)-ethyl2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate (16.5 g, 53.4 mmol) inCH₂Cl₂ (165 mL) at 0° C. was added TEA (11.2 ml, 80.2 mmol). Theresulting mixture was stirred for 10 min at 0° C. To this mixture wasadded Boc₂O (17.5 g, 80.2 mmol) in CH₂Cl₂ (10 mL) at 0° C. The reactionmixture was warmed to room temperature and stirred for 24 h. Additional1.16 g (5.32 mmol) of Boc₂O and 0.75 mL (5.35 mmol) of TEA were added.The resulting mixture was stirred for additional 24 h. The reactionmixture was quenched with water (65 mL). The organic layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (65 mL). The combinedorganic layers were washed with sat'd aq NaHCO₃ (2×100 mL) followed bybrine (100 mL). The organic layer was dried over MgSO₄, filtered risingwith CH₂Cl₂, and concentrated under reduced pressure to give the crudematerial that was treated with heptane (100 mL). The suspension of thecrude material in heptane was stirred for 1.5 h at room temperature,filtered, and rinsed with heptane to afford 19.0 g (87%) of(1E,4E)-ethyl8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate.MS APCI(+) m/z 409, 411 (M+1, Br pattern) detected.

Step D: Preparation of(1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylicacid

To a solution of (1E,4E)-ethyl8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate(15.0 g, 36.7 mmol) in THF (195 mL) at −15° C. was slowly added 1N aqNaOH (55.0 ml, 55.0 mmol) over 10 min. The reaction mixture was warmedto room temperature and stirred for 18 h. The reaction mixture waspoured into ice-cold water (500 mL). The pH of the mixture was carefullyadjusted to 5-6 with 0.5 N aq HCl (˜260 mL). The resulting mixture wasextracted with EtOAc. The aqueous layer was extracted with EtOAc (1×).The combined organic layers were washed with brine, dried over MgSO₄,filtered while rinsing with EtOAc, and concentrated under reducedpressure to give the crude material that was triturated with MeCN (20mL). The solids were filtered off and dried under reduced pressure toafford 7.56 g (54%) of the desired product. The filtrate wasconcentrated under reduced pressure again to give the second crudematerial that was triturated with MeCN again to afford additional 1.33 g(9.5%) of the product. Total 8.89 g (64%) of(1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylicacid was obtained. MS APCI(+) m/z 381, 383 (M+1, Br pattern) detected.

Step E: Preparation of tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamol)-3H-benzo[b]azepin-2-ylcarbamate

To a solution of dipropylamine (2.16 ml, 15.7 mmol) in CH₂Cl₂ (50 mL) at−10° C. was added EDCI (3.02 g, 15.7 mmol) followed bydiisopropylethylamine (2.97 ml, 17.1 mmol) over 5 min. The resultingmixture was stirred for 40 min at −15° C. To the reaction mixture wasadded(1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylicacid (5.00 g, 13.1 mmol) followed by HOBt (2.13 g, 15.7 mmol) over 5 minmaintaining the reaction temperature between −15 to −12° C. Theresulting mixture was warmed to room temperature and stirred for 19 h.The reaction mixture was poured onto water (50 mL). The organic layerwas separated and the aqueous layer was extracted with CH₂Cl₂ (50 mL).The combined organic layers were washed with sat'd aq NH₄Cl (75 mL). Theorganic layer was separated. The sat'd aq NH₄Cl solution was extractedwith CH₂Cl₂ (50 mL) again. The combined organic layers were washed withsat'd aq NaHCO₃ (2×75 mL) followed by brine (2×100 mL). The organiclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure to give the crude material that was taken into ether (50 mL)and kept in the freezer for 16 h. The precipitates were filtered off andthe filtrate was concentrated under reduced pressure to afford 4.64 g(76%) of tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate.MS APCI(+) m/z 464, 466 (M+1, Br pattern) detected.

Step F: Preparation of tert-butyl(1E,4E)-8-(4-(dimethylcarbamoyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate

To Na₂CO₃ (129 mg, 1.214 mmol) in a 50 mL round-bottom flask was addedwater (3.7 mL) was bubbled with N₂ for 10 min. To this mixture was addedtert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate(200 mg, 0.40 mmol) in EtOH (4.9 mL) at room temperature. The resultingmixture was bubbled with N₂ for 10 min. Pd(OAc)₂ (9.3 mg, 0.040 mmol)and 4,4′-(phenylphosphinidene)bisbenzenesulfonic acid dipotassiumhydrate (45 mg, 0.081 mmol) were added. The resulting mixture was warmedto 65° C. with N₂ bubbling. To this mixture was added a solution of4-(dimethylcarbamoyl)phenylboronic acid (97 mg, 0.49 mmol) in EtOH (0.6mL). The resulting mixture was stirred at 65° C. for 1 h. The reactionmixture was cooled to room temperature and concentrated under reducedpressure to give the crude material that was diluted with water (5 mL)and EtOAc (10 mL). The mixture was filtered through GF/F filter. Theaqueous layer was separated and extracted with EtOAc (10 mL). Thecombined organic layers were washed with brine (10 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure to give thecrude product that was purified by silica gel flash columnchromatography (CH₂Cl₂ to 2% MeOH in CH₂Cl₂) to afford 178 mg (83%) oftert-butyl(1E,4E)-8-(4-(dimethylcarbamoyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate.MS APCI(+) m/z 533 (M+1) detected.

Step G: Preparation of(1E,4E)-2-amino-8-(4-(dimethylcarbamoyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedure as described in Example101 (Step I). MS APCI(+) m/z 433 (M+1) detected; 1H-NMR (400 MHz, CDCl3)d 7.68 (d, 2H), 7.49-7.51 (m, 3H), 7.36 (d, 1H), 7.30 (dd, 1H), 6.83 (s,1H), 3.47 (br s, 4H), 3.13 (br s, 3H), 3.05 (br s, 3H), 2.81 (s, 2H),1.62-1.72 (m, 4H), 0.93 (t, 6H).

The following examples 125 and 126 were prepared by the procedures asdescribed in Example 124 (Steps F and G) using tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand the appropriate boronic acids.

Example 125

(1E,4E)-2-amino-8-(4-(diethylcarbamoyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 461 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.68 (d,2H), 7.50 (d, 1H), 7.45 (d, 2H), 7.36 (d, 1H), 7.30 (dd, 1H), 6.83 (s,1H), 3.56 (br s, 2H), 3.47 (br s, 4H), 3.33 (br s, 2H), 2.81 (s, 2H),1.62-1.72 (m, 4H), 1.25 (br s, 3H), 1.17 (br s, 3H), 0.93 (t, 6H).

Example 126

(1E,4E)-2-amino-8-(4-(piperidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 473 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.68 (d,2H), 7.46-7.50 (m, 3H), 7.36 (d, 1H), 7.29 (dd, 1H), 6.83 (s, 1H), 3.73(br s, 2H), 3.47 (br s, 6H), 2.81 (s, 2H), 1.62-1.70 (m, 10H), 0.93 (t,6H).

Example 127

(1E,4E)-2-amino-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of(R)-1-benzyl-3-(tert-butyldimethylsilyloxy)pyrrolidine

The title compound was prepared by the procedure as described in Example112 (Step A) using (R)-1-benzylpyrrolidin-3-ol.

Step B: Preparation of (R)-3-(tert-butyldimethylsilyloxy)pyrrolidine

The title compound was prepared by the procedure as described in Example112 (Step B) using(R)-1-benzyl-3-(tert-butyldimethylsilyloxy)pyrrolidine.

Step C: Preparation of(R)-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

The title compound was prepared by the procedure as described in Example101 (Step H) using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and(R)-3-(tert-butyldimethylsilyloxy)pyrrolidine.

Step D: Preparation of tert-butyl(1E,4E)-8-(4-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate

The title compound was prepared by the procedure as described in Example124 (Step F) using tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand(R)-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanone.MS APCI (+) m/z 689 (M+1) detected.

Step E: Preparation of tert-butyl(1E,4E)-4-(dipropylcarbamoyl)-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate

To a solution of tert-butyl(1E,4E)-8-(4-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate(225 mg, 0.327 mmol) in THF (4 mL) at 0° C. was added a solution of TBAF(0.34 mL, 0.34 mmol, 1 M solution in THF). The resulting mixture waswarmed to room temperature and stirred for 1.5 hr. The reaction mixturewas diluted with EtOAc and washed with brine (2×). The organic layer wasdried over MgSO₄, filtered, and concentrated under reduced pressure togive the crude tert-butyl(1E,4E)-4-(dipropylcarbamoyl)-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamatethat was used directly without further purification. MS APCI (+) m/z 575(M+1) detected.

Step F: Preparation of(1E,4E)-2-amino-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedure as described in Example101 (Step I) using tert-butyl(1E,4E)-4-(dipropylcarbamoyl)-8-(4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate.MS APCI (+) m/z 475 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) d 7.53-7.65(m, 5H), 7.33-7.38 (m, 2H), 6.84 (s, 1H), 4.60 (br s, 0.5H), 4.47 (br s,0.5H), 3.45-3.83 (m, 8H), 2.92 (s, 2H), 1.99-2.12 (m, 2H), 1.62-1.71 (m,4H), 0.93 (t, 6H).

Example 128

(1E,4E)-2-amino-8-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedures as described inExample 127 using tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand (S)-1-benzylpyrrolidin-3-ol. MS APCI (+) m/z 475 (M+1) detected;¹H-NMR (400 MHz, CDCl₃) d 7.53-7.66 (m, 5H), 7.32-7.38 (m, 2H), 6.84 (s,1H), 4.60 (br s, 0.5H), 4.47 (br s, 0.5H), 3.46-3.84 (m, 8H), 2.88 (s,2H), 1.99-2.11 (m, 2H), 1.62-1.71 (m, 4H), 0.93 (t, 6H).

The following examples 129 and 130 were prepared by the procedures asdescribed in Example 124 (Step F) and Example 101 (Step I) usingtert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanoneor((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanone.

Example 129

(1E,4E)-2-amino-8-(4-((3S,4S)-3,4-dihydroxypyrrolidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of (3S,4S)-pyrrolidine-3,4-diol

The title compound was prepared by the procedure as described in Example112 (Step B) using (3S,4S)-1-benzylpyrrolidine-3,4-diol.

Step B: Preparation of((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

The title compound was prepared by the procedure as described in Example101 (Step H) using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and(3S,4S)-pyrrolidine-3,4-diol.

Step C: Preparation of tert-butyl(1E,4E)-8-(4-((3S,4S)-3,4-dihydroxypyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate

The title compound was prepared by the procedure as described in Example124 (Step F) using tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone.MS APCI (+) m/z 591 (M+1) detected

Step D: Preparation of(1E,4E)-2-amino-8-(4-((3S,4S)-3,4-dihydroxypyrrolidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedure as described in Example109 (Step C) using tert-butyl(1E,4E)-8-(4-((3S,4S)-3,4-dihydroxypyrrolidine-1-carbonyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate:MS APCI (+) m/z 491 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) d 7.65 (d,2H), 7.57 (d, 2H), 7.47 (s, 1H), 7.34 (d, 1H), 7.27-7.29 (m, 1H), 6.82(s, 1H), 4.28 (s, 1H), 4.18 (s, 1H), 3.97-4.00 (m, 1H), 3.85-3.87 (m,1H), 3.66 (d, 1H), 3.46 (br s, 5H), 2.81 (s, 2H), 1.62-1.71 (m, 4H),0.93 (t, 6H).

Example 130

(1E,4E)-2-amino-8-(4-((3R,4R)-3,4-dihydroxypyrrolidine-1-carbonyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedures as described inExample 129 using tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand (3R,4R)-1-benzylpyrrolidine-3,4-diol. MS APCI (+) m/z 491 (M+1)detected; ¹H-NMR (400 MHz, CDCl₃) d 7.62 (d, 2H), 7.54 (d, 2H), 7.45 (s,1H), 7.32 (d, 1H), 7.24 (d, 1H), 6.80 (s, 1H), 4.25 (s, 1H), 4.14 (s,1H), 3.94-3.96 (m, 1H), 3.81-3.83 (m, 1H), 3.63 (d, 1H), 3.44 (br s,5H), 2.79 (s, 2H), 1.62-1.68 (m, 4H), 0.92 (t, 6H).

Example 133

(1E,4E)-2-amino-N,N-dipropyl-8-(pyridin-3-yl)-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 363 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 8.91 (d,1H), 8.59 (dd, 1H), 7.94 (dt, 1H), 7.49 (d, 1H), 7.35-7.40 (m, 2H), 7.29(dd, 1H), 6.84 (s, 1H), 3.47 (br s, 4H), 2.81 (s, 2H), 1.63-1.72 (m,4H), 0.94 (m, 6H).

Example 134

(1E,4E)-2-amino-N,N-dipropyl-8-(pyridin-4-yl)-3H-benzo[b]azepine-4-carboxamide

MS APCI (−) m/z 361 (M−1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 8.66 (d,2H), 7.55-7.57 (m, 3H), 7.39 (d, 1H), 7.33 (dd, 1H), 6.84 (s, 1H), 3.47(br s, 4H), 2.81 (s, 2H), 1.63-1.72 (m, 4H), 0.94 (m, 6H).

Example 135

(1E,4E)-2-amino-N,N-dipropyl-8-(pyrimidin-5-yl)-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedures as described inExample 101 (Step I) using tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate.MS APCI (+) m/z 364, 366 (M+1, Br pattern) detected

Step B: Preparation of(1E,4E)-2-amino-N,N-dipropyl-8-(pyrimidin-5-yl)-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedure as described in Example124 (Step F) using(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide,pyrimidin-5-ylboronic acid, and sodium2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate inH₂O-MeCN. MS APCI (+) m/z 364 (M+1) detected; 1H-NMR (400 MHz, CDCl₃) d9.21 (s, 111), 9.01 (s, 2H), 7.50 (s, 1H), 7.43 (d, 1H), 7.27-7.29 (m,1H), 6.84 (s, 1H), 3.47 (br s, 4H), 2.84 (s, 2H), 1.63-1.72 (m, 4H),0.94 (t, 6H).

Example 136

(1E,4E)-2-amino-8-(3-cyanophenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedure as described in Example124 (Step F) using(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideand 3-cyanophenylboronic acid. MS APCI (+) m/z 387 (M+1) detected;1H-NMR (400 MHz, CDCl₃) d 7.91 (m, 1H), 7.87-7.89 (m, 1H), 7.63-7.65 (m,1H), 7.55 (t, 1H), 7.51 (br s, 1H), 7.40 (d, 1H), 7.30 (dd, 1H), 6.85(s, 1H), 3.46 (br s, 4H), 2.90 (s, 2H), 1.62-1.72 (m, 4H), 0.94 (t, 6H).

The following examples 137 and 138 were prepared by the procedures asdescribed in Example 136 using(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideand 4-cyanophenylboronic acid or 3-(dimethylcarbamoyl)phenylboronicacid.

Example 137

(1E,4E)-2-amino-8-(4-cyanophenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 387 (M+1) detected; 1H-NMR (400 MHz, CDCl₃) δ 7.71-7.76(m, 4H), 7.52 (s, 1H), 7.39 (d, 1H), 7.31 (d, 1H), 6.84 (s, 1H), 3.46(br s, 4H), 2.86 (s, 2H), 1.62-1.72 (m, 4H), 0.93 (t, 6H).

Example 138

(1E,4E)-2-amino-8-(3-(dimethylcarbamoyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 433 (M+1) detected; 1H-NMR (400 MHz, CDCl₃) δ 7.68-7.69(m, 2H), 7.54 (br s, 1H), 7.46-7.50 (m, 1H), 7.40-7.42 (m, 1H), 7.37 (s,2H), 6.85 (s, 1H), 3.46 (br s, 4H), 3.14 (br s, 3H), 3.03 (br s, 3H),2.92 (s, 2H), 1.62-1.71 (m, 4H), 0.93 (t, 6H).

Example 139

Ethyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate

The title compound was prepared by the procedures as described inExample 124 (Step F) and Example 101 (Step I) using tert-butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand 4-(ethoxycarbonyl)phenylboronic acid. MS APCI (+) m/z 434 (M+1)detected; 1H-NMR (400 MHz, CDCl₃) δ 8.11 (d, 2H), 7.72 (d, 2H), 7.54 (d,1H), 7.38 (d, 1H), 7.34 (dd, 1H), 6.84 (s, 1H), 4.40 (q, 2H), 3.47 (brs, 4H), 2.83 (s, 2H), 1.62-1.72 (m, 4H), 1.42 (t, 3H), 0.94 (t, 6H).

Example 141

(1E,4E)-ethyl 2-amino-8-(pyridin-2-yl)-3H-benzo[b]azepine-4-carboxylateStep A: Preparation of2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

The title compound was prepared by the procedure as described in Example124 (Step F) using 4-bromo-2-nitrobenzaldehyde, bis(pinacolato)diboron,tris(dibenzylidineacetone)dipalladium(0), PCy₃, and KOAc in dioxane(reflux).

Step B: Preparation of 2-nitro-4-(pyridin-2-yl)benzaldehyde

The title compound was prepared by the procedure as described in Example101 (Step C) using2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and2-bromopyridine in dioxane (reflux).

Step C: Preparation of (E)-ethyl2-(cyanomethyl)-3-(2-nitro-4-(pyridin-2-yl)phenyl)acrylate

The title compound was prepared by the procedure as described in Example101 (Step D) using 2-nitro-4-(pyridin-2-yl)benzaldehyde andα-cyanomethylcarboethoxyethylidene triphenylphosphorane.

Step D: Preparation of (1E,4E)-ethyl2-amino-8-(pyridin-2-yl)-3H-benzo[b]azepine-4-carboxylate

The title compound was prepared by the procedure as described in Example101 (Step E) using (E)-ethyl2-(cyanomethyl)-3-(2-nitro-4-(pyridin-2-yl)phenyl)acrylate. MS APCI (+)m/z 308 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 8.70 (d, 1H), 7.85 (s,1H), 7.73-7.81 (m, 4H), 7.50 (d, 1H), 7.23-7.26 (m, 1H), 4.32 (q, 2H),2.98 (s, 2H), 1.38 (t, 3H).

The following examples 142 and 143 were prepared by the procedures asdescribed in Example 101 (Steps C, D, and E) using4-bromo-2-nitrobenzaldehyde and pyridin-3-ylboronic acid orpyridin-4-ylboronic acid.

Example 142

(1E,4E)-ethyl 2-amino-8-(pyridin-3-yl)-3H-benzo[b]azepine-4-carboxylate

MS APCI (+) m/z 308 (M+1) detected; ¹H-NMR (400 MHz, d₆-DMSO) δ 8.92 (s,1H), 8.58 (d, 1H), 8.11 (d, 1H), 7.80 (2, 1H), 7.58 (d, 1H), 7.49 (dd,1H), 7.36-7.38 (m, 2H), 4.26 (q, 2H), 2.98 (s, 2H), 1.32 (t, 3H).

Example 143

(1E,4E)-ethyl 2-amino-8-(pyridin-4-yl)-3H-benzo[b]azepine-4-carboxylate

MS APCI (+) m/z 308 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 8.66-8.68(m, 2H), 7.84 (s, 1H), 7.49-7.57 (m, 4H), 7.36 (dd, 1H), 4.33 (q, 2H),2.99 (s, 2H), 1.39 (t, 3H).

Example 144

(1E,4E)-ethyl2-amino-8-(pyrimidin-5-yl)-3H-benzo[b]azepine-4-carboxylate

The title compound was prepared by the procedure as described in Example124 (Step F) using (1E,4E)-ethyl2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate andpyrimidin-5-ylboronic acid. MS APCI (+) m/z 309 (M+1) detected; ¹H-NMR(400 MHz, CDCl₃) δ 9.22 (s, 1H), 9.02 (s, 2H), 7.84 (s, 1H), 7.54 (d,1H), 7.47 (d, 1H), 7.30 (dd, 1H), 4.34 (q, 2H), 2.99 (s, 2H), 1.40 (t,3H).

Example 145

(1E,4E)-ethyl 2-amino-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylateStep A: Preparation of (1E,4E)-ethyl2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate

A mixture of (1E,4E)-ethyl8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate(2.05 g, 5 mmol), 3-cyanophenylboronic acid (1.47 g, 10 mmol), CsF (2.28g, 15 mmol), and Pd(PPh₃)₄ (0.345 g, 0.3 mmol) in anhydrous THF (100 mL)was refluxed for 12 h. After cooling to room temperature, the reactionmixture was poured into water and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give the crude material that was purified by silicagel flash column chromatography to afford 1.12 g (52%) of (1E,4E)-ethyl2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate.

Step B: Preparation of (1E,4E)-ethyl2-amino-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate

The title compound was prepared by the procedure as described in Example101 (Step I) using (1E,4E)-ethyl2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate.MS APCI (+) m/z 332 (M+1) detected; ¹H-NMR (400 MHz, d₆-DMSO) δ 8.17 (s,1H), 8.04-8.06 (m, 1H), 7.82-7.84 (m, 1H), 7.78 (s, 1H), 7.67 (t, 1H),7.54 (d, 1H), 7.33-7.37 (m, 2H), 6.93 (s, 2H), 4.25 (q, 2H), 2.92 (s,2H), 1.31 (t, 3H).

The following examples 146 and 147 were prepared by the procedures asdescribed in Example 145. In case of example 146, Cs₂CO₃ was used as abase for the Suzuki coupling.

Example 146

(1E,4E)-ethyl 2-amino-8-(4-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate

MS APCI (+) m/z 332 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.83 (s,1H), 7.72-7.77 (m, 4H), 7.49 (d, 1H), 7.47 (d, 1H), 7.30 (dd, 1H), 4.33(q, 2H), 2.98 (s, 2H), 1.39 (t, 3H).

Example 147

(1E,4E)-ethyl2-amino-8-(3-(dimethylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate

MS APCI (+) m/z 378 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.83 (s,1H), 7.69-7.71 (m, 2H), 7.45-7.50 (m, 3H), 7.40-7.42 (m, 1H), 7.32 (dd,1H), 4.32 (q, 2H), 3.14 (br s, 3H), 3.02 (br s, 3H), 2.98 (s, 2H), 1.39(t, 3H).

The following examples 154, 155, and 156 were prepared by the proceduresas described in Example 101 (Steps C, D, and E) using4-bromo-2-nitrobenzaldehyde and the appropriate boronic acids.

Example 154

(1E,4E)-ethyl2-amino-8-(4-(dimethylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate

MS APCI (+) m/z 378 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.84 (s,1H), 7.69 (d, 2H), 7.46-7.51 (m, 4H), 7.32 (dd, 1H), 4.32 (q, 2H), 3.14(br s, 3H5), 3.05 (br s, 3H), 2.98 (s, 2H), 1.39 (t, 3H).

Example 155

(1E,4E)-ethyl2-amino-8-(4-(diethylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate

MS APCI (+) m/z 406 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.84 (s,1H), 7.68 (d, 2H), 7.44-7.49 (m, 4H), 7.32 (dd, 1H), 4.33 (q, 2H), 3.57(br s, 2H), 3.33 (br s, 2H), 2.98 (s, 2H), 1.39 (t, 3H), 1.25 (br s,3H), 1.17 (br s, 3H).

Example 156

(1E,4E)-ethyl2-amino-8-(4-(piperidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate

MS APCI (+) m/z 418 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.84 (s,1H), 7.68 (d, 2H), 7.46-7.48 (m, 4H), 7.32 (dd, 1H), 4.33 (q, 2H), 3.73(br s, 2H), 3.42 (br s, 2H), 2.98 (s, 2H), 1.62-1.70 (m, 6H), 1.39 (t,3H).

Example 174

(1E,4E)-2-amino-N-(2-hydroxybenzyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamidehydrochloride Step A: Preparation of methyl 2-hydroxybenzoate

To a solution of 2-hydroxybenzoic acid (110 g, 796 mmol) in MeOH (400mL) was bubbled HCl (gas) for 1 h. The resulting mixture was stirred at50° C. overnight. The reaction mixture was cooled to room temperatureand concentrated under reduced pressure to give the crude methyl2-hydroxybenzoate that was used directly without further purification.

Step B: Preparation of 2-hydroxy-N-propylbenzamide

The crude methyl 2-hydroxybenzoate was dissolved in n-propylamine (400mL). The reaction mixture in a sealed reactor was stirred at 80° C.overnight. The reaction mixture was concentrated under reduced pressureto give the crude material that was purified by silica gel flash columnchromatography to afford 120 g (84%) of 2-hydroxy-N-propylbenzamide.LCMS ESI (+) m/z 180 (M+1) detected.

Step C: Preparation of tert-butyl 2-hydroxybenzyl(propyl)carbamate

To a solution of LiAlH₄ (35 g, 0.92 mol) in THF (500 mL) at 0° C. wasadded 2-hydroxy-N-propylbenzamide (66 g, 0.37 mol) in THF (200 mL)dropwise. The reaction mixture was heated at 80° C. overnight. Thereaction mixture was quenched by addition of H₂O (300 mL) at 0° C. Then,Boc₂O (96.5 g, 0.44 mol) in THF (200 mL) was added dropwise. Afterstirring 5 h, sat'd aq NaHCO₃ (200 mL) was added. The aqueous layer wasseparated and extracted with EtOAc (2×300 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to give the crude material that was purified by silica gelflash column chromatography to afford 89 g (91%) of tert-butyl2-hydroxybenzyl(propyl)carbamate.

Step D: Preparation of 2-((propylamino)methyl)phenol hydrochloride

A solution of tert-butyl 2-hydroxybenzyl(propyl)carbamate (89 g, 0.34mol) in MeOH (400 mL) was bubbled with HCl gas. After stirring for 5 hat room temperature, the reaction mixture was concentrated under reducedpressure to afford 61 g (90%) of 2-((propylamino)methyl)phenol as HClsalt.

Step E: Preparation of tert-butyl(1E,4E)-4-((2-hydroxybenzyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate

The title compound was prepared by the procedure as described in Example101 (Step H) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and 2-((propylamino)methyl)phenol hydrochloride.

Step F: Preparation of(1E,4E)-2-amino-N-(2-hydroxybenzyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamidehydrochloride

A solution of the crude tert-butyl(1E,4E)-4-((2-hydroxybenzyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamatein anhydrous CH₂Cl₂ (15 mL) was bubbled with HCl (gas) for 4 h at 0° C.The resulting mixture was warmed to room temperature and stirred untilthe reaction was complete. The reaction mixture was concentrated underreduced pressure to give the crude material that was purified by silicagel flash column chromatography (EtOAc) to afford(1E,4E)-2-amino-N-(2-hydroxybenzyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamideas hydrochloride salt. MS APCI (+) m/z 523 (M+1) detected; 1H-NMR (400MHz, d₆-DMSO) δ 9.68 (br s, 1H), 7.76 (d, 2H), 7.64 (d, 2H), 7.59 (br s,3H), 7.10-7.14 (m, 2H), 7.03 (br s, 1H), 6.80-6.87 (m, 2H), 4.62 (br s,2H), 3.44-3.49 (m, 6H), 3.19 (br s, 2H), 1.83-1.89 (m, 4H), 1.56-1.57(m, 2H), 0.77-0.83 (m, 3H).

The following example, 176, was prepared by the procedures as describedin Example 101 (Step H) and Example 178 (Step C) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and N-(2-(propylamino)ethyl)methanesulfonamide or3-(propylamino)propane-1-sulfonamide.

Example 176

(1E,4E)-2-amino-N-(2-(methylsulfonamido)ethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

MS APCI (+) m/z 538 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 7.67 (d,2H), 7.60 (d, 2H), 7.47 (s, 1H), 7.35 (d, 1H), 7.28 (dd, 1H), 6.86 (s,1H), 3.66-3.69 (m, 4H), 3.51 (t, 2H), 3.42 (t, 4H), 2.90 (s, 5H),1.89-2.00 (m, 4H), 1.60-1.68 (m, 2H), 0.87 (t, 3H).

Example 178

(1E,4E)-2-amino-N-(2-amino-2-oxoethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of 2-(propylamino)acetamide hydrochloride

To a solution of propan-1-amine (236 g, 3.99 mol) in acetonitrile (100mL) at 0° C. was added a solution of 2-chloroacetamide (93.6 g, 1.00mol) in acetonitrile (1500 mL) over 3 h. The resulting mixture waswarmed to room temperature and stirred overnight. The reaction mixturewas concentrated under reduced pressure to give the crude material thatwas purified by re-crystallization (MeOH and CH₂Cl₂) to afford 80 g(69%) of 2-(propylamino)acetamide as HCl salt. LCMS ESI (+) m/z 117(M+1) detected.

Step B: Preparation of tert-butyl(1E,4E)-4-((2-amino-2-oxoethyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate

The title compound was prepared by the procedures as described inExample 101 (Step H) using(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid and 2-(propylamino)acetamide hydrochloride.

Step C: Preparation of(1E,4E)-2-amino-N-(2-amino-2-oxoethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide

A solution of the crude tert-butyl(1E,4E)-4-((2-amino-2-oxoethyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamatein anhydrous CH₂Cl₂ (15 mL) was bubbled with HCl (gas) for 4 h at 0° C.The resulting mixture was warmed to room temperature and stirred untilthe reaction was complete. To this mixture was added saturated NaHCO₃ at0° C. The aqueous layer was separated and extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the crude compound that waspurified by silica gel flash column chromatography (MeOH:CH₂Cl₂=1:50) toafford 225 mg (45%) of(1E,4E)-2-amino-N-(2-amino-2-oxoethyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide.MS APCI (+) m/z 474 (M+1) detected; 1H-NMR (400 MHz, CDCl3) d 7.67 (d,2H), 7.60 (d, 2H), 7.50 (br s, 1H), 7.30-7.36 (m, 2H), 6.93 (s, 1H),4.11 (s, 2H), 3.67 (t, 2H), 3.58 (br s, 2H), 3.50 (t, 2H), 2.87 (s, 2H),1.89-2.00 (m, 4H), 1.69-1.74 (m, 2H), 0.93 (t, 3H).

Example 182

(1E,4E)-2-amino-N-(3-hydroxypropyl)-8-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N-propyl-3H-benzo[b]azepine-4-carboxamideStep A: Preparation of tert-butyl(1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate

The title compound was prepared by the procedure as described in Example101 (Step H) using(1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylicacid and 3-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS APCI(+) m/z 594, 596 (M+1, Br pattern) detected.

Step B: Preparation of tert-butyl(1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate

The title compound was prepared by the procedure as described in Example124 (Step F) using tert-butyl(1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamateand(S)-(3-hydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanonethat was prepared by the procedure as described in Example 101 (Step H)using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and(S)-pyrrolidin-3-ol. MS APCI (+) m/z 705 (M+1) detected.

Step C: Preparation of(1E,4E)-2-amino-N-(3-hydroxypropyl)-8-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-N-propyl-3H-benzo[b]azepine-4-carboxamide

The title compound was prepared by the procedure as described in Example109 (Step C) using tert-butyl(1E,4E)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-8-(4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate.MS APCI (+) m/z 491 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) d 7.59-7.66(m, 4H), 7.50 (s, 1H), 7.36 (d, 1H), 7.31 (d, 1H), 6.88 (s, 1H), 4.61(br s, 0.5H), 4.48 (br s, 0.5H), 3.75-3.84 (m, 2H), 3.62-3.70 (m, 6H),3.46-3.50 (m, 2H), 2.84 (s, 2H), 1.96-2.15 (m, 4H), 1.82-1.87 (m, 2H),1.65-1.72 (m, 2H), 0.93 (t, 3H).

Example 186

3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoicacid Step A

Benzyl3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(52%) was prepared according to Example 206, Step B, substituting3-(benzyloxycarbonyl)phenylboronic acid for4-(methoxycarbonyl)phenylboronic acid. m/z (APCI-pos) M+1=496.2.

Step B

3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoicacid (61%) was prepared according to Example 188, Step B, substitutingbenzyl3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoatefor benzyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.42 (m, 1H), 8.00-8.06 (m, 1H),7.81-7.87 (m, 1H), 7.68-7.73 (m, 1H), 7.51-7.63 (m, 3H), 6.96 (s, 1H),3.51 (s, 2H), 3.15-3.41 (m, 4H, partially obscured by water peak),1.53-1.68 (m, 4H), 0.75-0.94 (m, 6H); m/z (APCI-pos) M+1=406.2.

Example 187

Ethyl3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoateStep A

Ethyl3-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(45%) was prepared according to Example 206, Step B, substituting3-(methoxycarbonyl)phenylboronic acid for4-(methoxycarbonyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ8.34-8.37 (m, 1H), 8.02-8.05 (m, 1H), 7.82-7.86 (m, 1H), 7.49-7.55 (m,2H), 7.33-7.39 (m, 2H), 6.84 (s, 1H), 5.17 (br s, 1H), 4.37-4.45 (m,2H), 3.36-3.55 (m, 4H), 2.84 (s, 2H), 1.62-1.72 (m, 4H), 1.38-1.45 (m,3H), 0.89-0.98 (m, 6H); m/z (APCI-pos) M+1=434.3.

Example 188

4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoicacid Step A

Benzyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(31%) was prepared according to Example 206, Step B, substituting4-(benzyloxycarbonyl)phenylboronic acid for4-(methoxycarbonyl)phenylboronic acid. m/z (APCI-pos) M+1=496.2.

Step B

Benzyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(0.025 g, 0.0504 mmol) was suspended in 1 ml of methanol, and 25 mgs of10% Pd/C (Degussa type) was added and the mixture was hydrogenated undera balloon of hydrogen for one hour. This mixture was then filteredthrough GF/F filter paper, and the filtrate was concentrated to 16 mgsof4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoicacid (78%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.98-8.03 (m, 2H), 7.76-7.82 (m,2H), 7.38-7.43 (m, 1H), 7.33-7.37 (m, 1H), 7.27-7.31 (m, 1H), 6.92 (brs, 1H), 6.76 (s, 1H), 3.28-3.36 (m, 4H, partially obscurred by waterpeak), 2.74 (s, 2H), 1.51-1.62 (m, 4H), 0.71-0.97 (m, 6H); m/z(APCI-pos) M+1=406.2.

Example 190

Ethyl 4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate Step A

Ethyl4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(44%) was prepared according to Example 206, Step B, substitutingtert-butyl(1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propypcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamatefor 1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideand 4-(ethoxycarbonyl)phenylboronic acid for4-(methoxycarbonyl)phenylboronic acid. m/z (APCI-pos) M+1=664.0

Step B

Ethyl4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propypcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(0.050 g, 0.075 mmol) was dissolved in 2 mls of dichloromethane and 0.5ml of TFA. After about one hour, the mixture was concentrated underreduced pressure and the resulting residue was then re-dissolved indichloromethane and 1 ml of concentrated ammonium hydroxide added andthe mixture vigorously stirred for 15 minutes. This mixture was thendiluted with water, extracted with dichloromethane (2×), extracts driedover sodium sulfate and concentrated under reduced pressure. Preparativethin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH₄OH)afforded 0.012 g (35%) of ethyl4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.¹H NMR (400 MHz, CDCl₃) δ 8.08-8.14 (m, 2H), 7.69-7.74 (m, 2H),7.52-7.55 (m, 1H), 7.32-7.40 (m, 2H), 6.89 (s, 1H), 4.35-4.44 (m, 2H),3.58-3.71 (m, 5H), 3.45-3.53 (m, 2H), 2.85 (s, 2H), 1.81-1.88 (m, 2H),1.64-1.77 (m, 2H), 1.36-1.44 (m, 3H), 0.90-0.97 (m, 3H); m/z (APCI-pos)M+1=450.2.

Example 194

(1E,4E)-2-amino-8-(3-hydroxyphenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideStep A

(1E,4E)-2-amino-8-(3-hydroxyphenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide(39%) was prepared according to Example 206, Step B, substituting3-hydroxyphenylboronic acid for 4-(methoxycarbonyl)phenylboronic acid.¹H NMR (400 MHz, CDCl₃) δ 7.59-7.64 (m, 1H), 7.24-7.38 (m, 4H),7.08-7.14 (m, 1H), 6.81-6.86 (m, 2H), 5.10 (br s, 2H), 3.35-3.35 (m,4H), 2.86 (s, 2H), 1.58-1.71 (m. 4H), 0.80-0.98 (m, 6H); m/z (APCI-pos)M+1=378.2.

Example 195

(1E,4E)-2-amino-8-(4-hydroxyphenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideStep A

tert-Butyl(1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate(0.095 g, 0.205 mmol), 4-hydroxyphenylboronic acid (0.040 g, 0.286mmol), Pd(OAc)₂ (0.0045 g, 0.020 mmol),4,4′-(phenylphosphinidene)bisbenzenesulfonic acid dipotassium hydrate(0.022 g, 0.041 mmol), 2M sodium carbonate solution (0.307 mls, 0.614mmol) were combined in 2 mls of ethanol and this mixture was purged withArgon for 5 minutes and then warmed to 65° C. under argon for 1.5 hours.The mixture was then diluted with citric acid, extracted with EtOAc(2×), extracts washed with saturated sodium carbonate solution, driedover sodium sulfate and concentrated under reduced pressure. Flash 40Biotage (40S cartridge, 30% EtOAc/Hexane) afforded 0.040 g of tert-butyl(1E,4E)-4-(dipropylcarbamoyl)-8-(4-hydroxyphenyl)-3H-benzo[b]azepin-2-ylcarbamate(41%). m/z (APCI-pos) M+1=478.0.

Step B

tert-Butyl(1E,4E)-4-(dipropylcarbamoyl)-8-(4-hydroxyphenyl)-3H-benzo[b]azepin-2-ylcarbamate(0.040 g, 0.084 mmol) was dissolved in 1 ml of dichloromethane. 0.5 mlof TFA was then added and the mixture was stirred at room temperaturefor one hour. The reaction was then quenched by the addition ofsaturated sodium bicarbonate solution and stirred for 15 minutes, thenextracted twice with dichloromethane, extracts dried over sodium sulfateand concentrated. Preparative thin layer chromatography (0.5 mm plate,7% MeOH/DCM) afforded 6 mgs (19%) of(1E,4E)-2-amino-8-(4-hydroxyphenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideas a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.53 (m, 2H),7.41-7.44 (m, 1H), 7.30-7.33 (m, 1H), 6.88-6.93 (m, 2H), 6.83 (s, 2H),3.42-3.54 (m, 4H), 2.81 (s, 2H), 1.61-1.72 (m, 4H), 0.89-0.97 (m, 6H);m/z (APCI-pos) M+1=378.2.

Example 202

(1E,4E)-2-Amino-N-(3-fluoropropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamideStep A

tert-Butyl(1E,4E)-4-((3-fluoropropyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate(19%) was prepared according to Example 208, Step D, substituting(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylicacid for(1E,4E)-8-Bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylicacid. m/z (APCI-pos) M+1=577.0.

Step B

(1E,4E)-2-Amino-N-(3-fluoropropyl)-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide(45%) was prepared according to Example 208, Step F, substitutingtert-butyl(1E,4E)-4-((3-fluoropropyl)(propyl)carbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamatefor ethyl4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.¹H NMR (400 MHz, DMSO-d₆) δ 7.70-7.76 (m, 2H), 7.57-7.64 (m, 2H),7.36-7.42 (m, 1H), 7.24-7.34 (m, 2H), 6.78-6.84 (m, 3H), 4.40-4.61 (m,2H), 3.43-3.52 (m, 6H), 2.75 (s, 2H), 1.79-1.96 (m, 6H), 1.53-1.63 (m,2H), 0.79-0.90 (m, 3H); m/z (APCI-pos) M+1=477.3.

Example 203

Ethyl2-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoateStep A

Ethyl2-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(24%) was prepared according to Example 206, Step B, substituting2-(methoxycarbonyl)phenylboronic acid for4-(methoxycarbonyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ7.83-7.86 (m, 1H), 7.49-7.55 (m, 1H), 7.38-7.45 (m, 2H), 7.23-7.29 (m,2H), 6.98-7.01 (m, 1H), 6.83 (s, 1H), 5.28 (br s, 1H), 4.08-4.16 (m,2H), 3.41-3.51 (m, 4H), 2.82 (s, 2H), 1.61-1.72 (m, 4H), 1.00-1.05 (m,3H), 0.90-0.97 (m, 6H); m/z (APCI-pos) M+1=434.2.

Example 204

Ethyl2-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoateStep A

Ethyl2-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(30%) was prepared according to Example 190, Steps A and B, substituting2-(ethoxycarbonyl)phenylboronic acid for 4-(ethoxycarbonyl)phenylboronicacid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.57-7.76 (m, 2H), 7.43-7.56 (m, 2H),7.28-7.39 (m, 1H), 6.74-7.01 (m, 5H), 4.43-4.55 (m, 1H), 3.98-4.14 (m,2H), 3.26-3.55 (m, 6H, partially obstructed by water peak), 2.74 (s,2H), 1.67-1.82 (m, 2H), 1.49-1.66 (m, 2H), 0.71-1.02 (m, 6H); m/z(APCI-pos) M+1=450.2.

Example 206

Methyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoateStep A

A 50 ml round bottom flask equipped with a stir bar and nitrogen inletwas charged with 15 mls of dry toluene and dipropylamine (0.44 ml, 3.24mmol). This was chilled to 0° C. and AlMe₃ (4.04 mls, 8.09 mmol, 2M intoluene) was then added. Once the addition was complete, the mixture wasallowed to warm to room temperature (˜20-30 minutes). (1E,4E)-ethyl2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate (0.5 g, 1.62 mmol) wasthen added portionwise resulting in a dark solution. This mixture waswarmed to 100° C. for about 16 hours, and then allowed to cool to roomtemperature. This mixture was then poured into 50 mls of a 30% aq.solution of Rochelle's salt and vigorously stirred for 20 minutes, thenextracted with EtOAc (2×), extracts dried over sodium sulfate andconcentrated under reduced pressure. Flash 40 Biotage (40M cartridge, 5%MeOH/DCM) afforded 201 mgs (32%) of(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide.m/z (APCI-pos) M+1=364.2, 366.2.

Step B

(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide(75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs,0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) werecombined in 2 mls of acetonitrile in a microwave reaction vial. Thismixture was heated in a microwave to 100° C. for 30 minutes. The mixturewas then diluted with EtOAc, washed twice with brine, dried over sodiumsulfate, and concentrated under reduced pressure. Preparative thin layerchromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 20 mgs (23%) ofmethyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.¹H NMR (400 MHz, CDCl₃) δ 8.08-8.13 (m, 2H), 7.68-7.74 (m, 2H),7.52-7.56 (m, 1H), 7.33-7.39 (m, 2H), 6.84 (s, 1H), 3.94 (s, 3H),3.60-3.68 (m, 2H), 3.37-3.51 (m, 4H), 2.86 (s, 2H), 1.60-1.72 (m, 4H),0.88-0.98 (m, 6H); m/z (APCI-pos) M+1=420.2.

Example 207

Ethoxymethyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoateStep A

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.50 g,2.02 mmol) was dissolved in 20 mls of dry acetonitrile. To this solutionwas added powdered potassium carbonate (0.42 g, 3.02 mmol) followed bychloromethyl ethyl ether (0.24 mls, 2.42 mmol). This mixture was warmedto 65° C. for 2 hours, then allowed to cool to room temperature,filtered and the filtrate concentrated to give ethoxymethyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as a solid(84%). This material was taken onto the next step without furtherpurification.

Step B

Ethoxymethyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(17%) was prepared according to Example 206, Step B, substitutingethoxymethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate for4-(methoxycarbonyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ8.12-8.17 (m, 2H), 7.72-7.76 (m, 2H), 7.54-7.56 (m, 1H), 7.33-7.40 (m,2H), 6.84 (s, 1H), 5.57 (s, 2H), 3.78-3.85 (m, 2H), 3.61-3.70 (m, 2H),3.36-3.53 (m, 4H), 2.84 (s, 2H), 1.58-1.74 (m, 4H), 1.26-1.31 (m, 3H),0.89-0.99 (m, 6H); m/z (APCI-pos) M+1=464.2.

Example 208

Ethyl4-((1E,4E)-2-amino-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoateStep A

3-Fluoropropan-1-amine hydrochloride (1.00 g, 8.81 mmol) was dissolvedin 90 mls of dry dichloromethane. To this was added di-t-butyldicarbonate (2.11 g, 9.69 mmol) and triethylamine (2.70 mls, 19.37mmol). This mixture was stirred at room temperature for 16 hours, thenwashed with 1N aq. HCl (1×), saturated sodium bicarbonate solution (1×),dried over sodium sulfate and concentrated under reduced pressure togive 1.6 g (100%) of tert-butyl 3-fluoropropylcarbamate as a clear andcolorless oil.

Step B

tert-Butyl 3-fluoropropylcarbamate (1.6 g, 9.03 mmol) was dissolved in90 mls of dry DMF. To this solution was added sodium hydride (1.44 g,36.12 mmol, 60% dispersion in mineral oil) and the mixture was stirredat room temperature for 20 minutes. Iodopropane (3.17 mls, 27.09 mmol)was then added and the mixture was warmed to 65° C. for 10 hours, thenquenched with saturated ammonium chloride solution. This was extractedwith EtOAc (2×), extracts washed twice with brine, dried over sodiumsulfate and concentrated to 2 g (100%) of tert-butyl3-fluoropropyl(propyl)carbamate as a clear oil.

Step C

tert-Butyl 3-fluoropropyl(propyl)carbamate (2.00 g, 9.12 mmol) wasdissolved in 90 mls of ether. This mixture was chilled to 0° C. and HClgas was bubbled in to the reaction mixture for 15 minutes, reactionvessel capped and the mixture allowed to warm to room temperature, andstirred for 6 hours. The mixture was then concentrated to a stickysolid, giving 1.6 g (99%) of 3-fluoro-N-propylpropan-1-aminehydrochloride.

Step D

(1E,4E)-8-Bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylicacid (0.275 g, 0.721 mmol) was dissolved in 7 mls of dry DMF. To thissolution was added HOBT (0.107 g, 0.794 mmol) and EDCI (0.152 mmol,0.794 mmol), and this mixture was stirred at room temperature for 20minutes. 3-Fluoro-N-propylpropan-1-amine hydrochloride (0.124 mmol,0.794 mmol) followed by triethylamine (0.211 mls, 1.515 mmol) were thenadded and the reaction mixture stirred at room temperature for 16 hours.The mixture was then diluted with EtOAc, washed several times withbrine, dried over sodium sulfate and concentrated under reducedpressure. Flash 40 Biotage (40S cartridge, 25% EtOAc/Hexane) afforded0.089 g (26%) of tert-butyl(1E,4E)-8-bromo-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate.m/z (APCI-pos) M+1=481.8 and 483.8.

Step E

Ethyl4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoatewas prepared according to Example 206, Step B, substituting tert-butyl(1E,4E)-8-bromo-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamatefor(1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamideand 4-(ethoxycarbonyl)phenylboronic acid for4-(methoxycarbonyl)phenylboronic acid. m/z (APCI-pos) M+1=551.9.

Step F

The crude product from Step E was then taken up in 2 mls ofdichloromethane and 1 ml of TFA, and stirred at room temperature for onehour. The mixture was concentrated under reduced pressure and theresulting crude product was taken up in DCM (10 mls) and concentratedammonium hydroxide (5 mls) and stirred at room temperature for 15minutes, then extracted with dichloromethane. The extracts were driedover sodium sulfate and concentrated under reduced pressure. Preparativethin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM/0.5% NH₄OH)afforded 17 mgs (36%) of ethyl4-((1E,4E)-2-amino-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.¹H NMR (400 MHz, CDCl₃) δ 8.09-8.14 (m, 2H), 7.70-7.74 (m, 2H),7.52-7.55 (m, 1H), 7.32-7.41 (m, 2H), 6.87 (m, 1H), 5.11 (br s, 1H),4.57-4.63 (m, 1H), 4.46-4.52 (m, 1H), 4.37-4.45 (m, 2H), 3.57-3.73 (m,2H), 3.42-3.55 (m, 2H), 2.82 (s, 2H), 1.99-2.15 (m, 2H), 1.62-1.76 (m,2H), 1.38-1.45 (m, 3H), 0.89-0.98 (m, 3H); m/z (APCI-pos) M+1=452.2.

Example 209

4-((1E,4E)-2-Amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoicacid Step A

Benzyl4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate(8%) was prepared according to Example 190, Steps A and B, substituting4-(benzyloxycarbonyl)phenylboronic acid for4-(ethoxycarbonyl)phenylboronic acid.

Step B

4-((1E,4E)-2-Amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8yl)benzoicacid (63%) was prepared according to Example 188, Step B, substitutingbenzyl4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoatefor benzyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.m/z (APCI-pos) M+1=422.3.

Example 210

Ethyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)-2-fluorobenzoateStep A

Ethyl4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)-2-fluorobenzoate(32%) was prepared according to Example 206, Step B, substituting3-fluoro-4-(methoxycarbonyl)phenylboronic acid for4-(methoxycarbonyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ7.97-8.02 (m, 1H), 7.47-7.53 (m, 2H), 7.29-7.43 (m, 3H), 6.89 (s, 1H),4.36-4.46 (m, 2H), 3.56-3.68 (m, 2H), 3.38-3.50 (m, 4H), 2.84 (s, 2H),1.60-1.71 (m, 4H), 1.38-1.44 (m, 3H), 0.90-0.97 (m, 6H); m/z (APCI-pos)M+1=452.2.

Example 211

Ethyl4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)-2-fluorobenzoateStep A

Ethyl4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)-2-fluorobenzoate(19%) was prepared according to Example 190, Steps A and B, substituting4-(ethoxycarbonyl)-3-fluorophenylboronic acid for4-(ethoxycarbonyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ7.97-8.04 (m, 1H), 7.47-7.52 (m, 2H), 7.36-7.45 (m, 2H), 7.29-7.33 (m,1H), 6.88 (s, 1H), 5.19 (br s, 1H), 4.38-4.47 (m, 2H), 3.59-3.72 (m,5H), 3.45-3.52 (m, 2H), 2.84 (s, 2H), 1.79-1.90 (m, 2H), 1.67-1.76 (m,2H), 1.40-1.42 (m, 3H), 0.89-0.97 (m, 3H); m/z (APCI-pos) M+1=468.2.

Example 212

Methyl5-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)picolinate

Step A

Methyl5-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)picolinate(17%) was prepared according to Example 206, Step B, substituting methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate for4-(methoxycarbonyl)phenylboronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.89(s, 1H), 8.98-9.10 (s, 1H), 8.32-8.36 (m, 1H), 8.18-8.22 (m, 1H),7.71-7.89 (m, 3H), 7.06 (s, 1H), 3.93 (s, 3H), 3.23-3.40 (m, 4H),1.53-1.63 (m, 4H), 0.75-0.97 (m, 6H); m/z (APCI-pos) M+1=421.2.

Example 220

(E)-Ethyl3-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acrylateStep A

(E)-Ethyl3-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acrylate(40%) was prepared according to Example 190, Steps A and B, substituting(E)-4-(3-ethoxy-3-oxoprop-1-enyl)phenylboronic acid for4-(ethoxycarbonyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ7.67-7.75 (m, 3H), 7.58-7.62 (m, 2H), 7.51-7.53 (m, 1H), 7.30-7.39 (m,2H), 6.88 (s, 1H), 6.48 (d, 1H), 5.11 (br s, 1H), 4.24-4.32 (m 2H),3.58-3.70 (m, 4H), 2.82 (s, 2H), 1.78-1.89 (m, 2H), 1.66-1.78 (m, 2H),1.30-1.40 (m, 3H), 0.89-0.99 (m, 3H); m/z (APCI-pos) M+1=476.2.

Example 2 HEK/TLR Assays

The activity of the compounds of this invention may be determined by thefollowing assays.

The HEK-293 hTLR transfectant assay employs HEK293 cells stablytransfected with various hTLRs and transiently co-transfected with aplasmid containing an NF-κB driven secreted embryonic alkaline phosphate(SEAP) reporter gene. Stimulation of TLRs activates their downstreamsignaling pathways and induces nuclear translocation of thetranscription factor NF-κB. Reporter gene activity is then measuredusing a spectrophotometric assay.

To measure agonist activity, human embryonic kidney (HEK) cells whichstably express various human TLR genes, including TLR7 and TLR8, and aNFkB-luciferase reporter gene (e.g., 293XL-hTLR8 cells available fromInvivoGen, San Diego, Calif.) are prepared according to supplier'sinstructions and incubated with various concentrations of test compoundovernight. The amount of induced luciferase is measured by reading theabsorbance at 650 mu. Agonist compounds of the invention have an MC₅₀ of25 μM or less, wherein MC₅₀ is defined as the concentration at which 50%of maximum induction is seen.

Example 3 PBMC Assays for TLR7 and TLR8

Peripheral blood mononuclear cells (PBMCs) from human blood wereisolated using BD Vacutainer Cell Preparation Tubes with sodium citrate.Cells were incubated with compound overnight. TLR8 activity was assayedby measuring the amount of TNFα in supernatants by ELISA. TLR7 activitywas assayed by measuring the amount of IFNα in supernatants by ELISA(R&D Systems). Compounds of this invention had an MC₅₀ of 100 or less,wherein MC₅₀ is the concentration at which 50% of the maximum inductionis seen. The results of this assay are shown below in Tables 2 and 3.

MC₅₀ numbers are represented as factors of ten, for example, + indicatesan MC₅₀ value of X 10⁴, or a value in the tens of thousands of nanomolar(nM range); ++ indicates an MC₅₀ value of X 10³, or a value in thethousands; +++ indicates an MC₅₀ value of X 10², or a value in thehundreds; and ++++ indicates an MC₅₀ value of X 10¹ or 10⁰, or a valuein the tens or ones.

TABLE 2 Cmpd TLR8 # Structure MC₅₀ 141

+++ 142

++++ 143

++++ 144

++++ 145

++++ 146

+++ 147

+++ 154

+++ 155

+++ 156

+++ 101

+++ 102

+++ 103

++ 104

++++ 105

++++ 106

++++ 107

++++ 109

++++ 110

++ 112

++ 117

+++ 119

+++ 120

++ 174

+++ 176

++ 178

+++ 127

++++ 128

++++ 129

+++ 130

+++ 182

++++ 115

++ 121

+ 122

++ 124

+++ 125

+++ 126

+++ 133

++++ 134

+++ 135

++++ 136

++++ 137

++++ 138

++++ 139

+++ 186

+ 187

+++ 188

++ 190

+++ 194

+++ 195

+++ 202

+++ 203

+++ 204

+++ 206

+++ 207

++ 208

++ 209

+ 210

+++ 211

+++ 212

+++ 220

+++

TABLE 3 Cmpd TLR7 # Structure MC₅₀ 142

++ 144

++ 147

++ 103

++ 104

++ 105

++ 106

++ 109

++ 112

+ 117

+ 119

++ 174

++ 178

+++ 127

++ 128

++ 182

++ 124

++ 125

++ 126

++ 133

++ 134

++ 135

+++ 136

++ 137

+ 138

++ 139

++ 190

+ 194

++ 195

+++ 203

++ 204

++ 206

++ 207

++ 210

++ 211

++ 212

++ 220

+

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

Unless otherwise noted, all references listed herein are specificallyincorporated by reference.

What is claimed is:
 1. A compound having the formula II:

or a tautomer, enantiomer or salt thereof, wherein W is H or —OH; Z is Hor —OH; and when W is H, Z is —OH, and when W is —OH, Z is H or —OH; R²is selected from OR¹⁴ and NR⁶R⁷; R⁶ and R⁷ are each independentlyselected from H, alkyl, cycloalkyl, heterocycle or benzyl, wherein saidalkyl, cycloalkyl, or benzyl is optionally substituted with one or moregroups independently selected from —F, —OR⁸, —NR¹²SO₂R¹³, —C(═O)NR¹²R¹³or R⁶ and R⁷ together with the nitrogen atom to which they are attachedform a heterocyclic ring, further wherein said heterocyclic ring isoptionally substituted with one or more —OH; R⁸ is selected fromhydrogen and alkyl, and R¹², R¹³ and R¹⁴ are each independently selectedfrom H and alkyl, wherein said alkyl is optionally substituted with —OH;and n is 1 or
 2. 2. A compound having the formula VIIa:

or a tautomer, enantiomer or salt thereof, wherein: v is 0, 1, or 2; R⁶and R⁷ are each independently propyl, wherein one of R⁶ or R⁷ issubstituted with one or more —OH and the other is unsubstituted.
 3. Thecompound of claim 2, wherein v is
 1. 4. A compound selected from thegroup consisting of:

and tautomers, enantiomers and salts thereof.
 5. The compound of claim4, selected from the group consisting of:

and tautomers, enantiomers and salts thereof.
 6. The compound of claim1, wherein the salt is a pharmaceutically acceptable salt.
 7. Apharmaceutical composition, which comprises a compound of claim 1 or atautomer, enantiomer or salt thereof together with a pharmaceuticallyacceptable diluent or carrier.
 8. A method of treating cancer,comprising administering to a patient in need thereof an effectiveamount of a compound of claim 1 or a tautomer, enantiomer or saltthereof such that said cancer is treated, wherein said cancer isselected from biliary tract cancer, brain cancer, breast cancer,cervical cancer, choriocarcinoma, colon cancer, endometrial cancer,esophageal cancer, gastric cancer, intraepithelial neoplasms, leukemia,lymphoma, liver cancer, lung cancer, melanoma, neuroblastomas, oralcancer, ovarian cancer, pancreatic cancer, prostate cancer, rectalcancer, renal cancer, sarcomas, skin cancer, testicular cancer, thyroidcancer, other carcinomas and sarcomas.
 9. A method of treating allergy,comprising administering to a patient in need thereof an effectiveamount of a compound of claim 1 or a tautomer, enantiomer or saltthereof such that said allergy is treated.
 10. The method of claim 9,wherein said allergy is acquired hypersensitivity to an allergen,eczema, allergic rhinitis or coryza, hay fever, asthma, urticaria(hives), food allergies, or other atopic conditions.
 11. The compound ofclaim 1 having the formula IIa:

(IIa) or a tautomer, enantiomer or salt thereof.
 12. The compound ofclaim 1, wherein R² is NR⁶R⁷.
 13. The compound of claim 12, wherein oneof R⁶ or R⁷ is H and the other is alkyl, or both R⁶ and R⁷ are eachindependently alkyl optionally substituted with one or more —OH.
 14. Thecompound of claim 12, wherein R⁶ and R⁷ are both propyl.
 15. Thecompound of claim 12, wherein R⁶ and R⁷ together with the nitrogen atomto which they are attached form a heterocyclic ring, further whereinsaid heterocyclic ring is optionally substituted with one or more —OH.16. The compound of claim 2, wherein v is
 0. 17. The compound of claim2, wherein the salt is a pharmaceutically acceptable salt.
 18. Apharmaceutical composition, which comprises a compound of claim 2 or atautomer, enantiomer or salt thereof together with a pharmaceuticallyacceptable diluent or carrier.
 19. The compound of claim 4, wherein thesalt is a pharmaceutically acceptable salt.
 20. A pharmaceuticalcomposition, which comprises a compound of claim 4 or a tautomer,enantiomer or salt thereof together with a pharmaceutically acceptablediluent or carrier.